Dihydrobenzopyrans, dihydrobenzothiopyrans, and tetrahydroquinolines for the treatment of cox-2 mediated disorders

ABSTRACT

A class of dihydrobenzopyrans, dihydrobenzothiopyrans, tetrahydroquinolines, tetraydronaphthalenes, and analogs thereof, is described for use in treating cyclooxygenase-2 mediated disorders. Compounds of particular interest are defined by Formula (I) wherein X, A 1 , A 2 , A 3 , A 4 , R, R″, R 1  and R 2  are as described in the specification.

FIELD OF THE INVENTION

[0001] This invention is in the field of anti-inflammatorypharmaceutical agents and specifically relates to compounds,compositions and methods for treating cyclooxygenase-2 mediateddisorders, such as inflammation and inflammation-related disorders.

BACKGROUND OF THE INVENTION

[0002] Prostaglandins play a major role in the inflammation process andthe inhibition of prostaglandin production, especially production ofPGG₂, PGH₂ and PGE₂, has been a common target of antiinflammatory drugdiscovery. However, common non-steroidal antiinflammatory drugs (NSAIDs)that are active in reducing the prostaglandin-induced pain and swellingassociated with the inflammation process are also active in affectingother prostaglandin-regulated processes not associated with theinflammation process. Thus, use of high doses of most common NSAIDs canproduce severe side effects, including life threatening ulcers, thatlimit their therapeutic potential. An alternative to NSAIDs is the useof corticosteroids, which have even more drastic side effects,especially when long term therapy is involved.

[0003] Previous NSAIDs have been found to prevent the production ofprostaglandins by inhibiting enzymes in the human arachidonicacid/prostaglandin pathway, including the enzyme cyclooxygenase (COX).The recent discovery of an inducible enzyme associated with inflammation(named “cyclooxygenase-2 (COX-2)” or “prostaglandin G/H synthase II”)provides a viable target of inhibition which more effectively reducesinflammation and produces fewer and less drastic side effects.

[0004] Recently, there has been significant research into some of theroles of cyclooxygenase-2. It has been found that COX-2 is upregulatedin benign and malignant tumors (K. Subbaramaiah et al., Proc. Soc. Exp.Biol. Med., 216, 201 (1997)) including lung cancer (T. Hida et al.,Anticancer Res., 18, 775-82 (1998)), Barrett's esophagus (K. Wilson,Cancer Res., 58, 2929-34 (1998)) and skin cancer (S. Buckman et al.,Carcinogenesis, 19, 723-29 (1998)). It is expressed in airway cells withimplication in asthma (P. Barnes et al., Lung Biol. Health Dis., 114,111-27 (1998)). Cox-2 also has a role in pre-term labor, angiogenesis(M. Tsujii et al. Cell, 93, 705-16 (1998)), vascular rejection (M.Bustos, J. Clin. Invest., 100, 1150-58 (1997)), HIV induced apoptosis(G. Bagetta et al., Biochem. Biophys. Res. Commun., 244, 819-24 (1998)),neurodegeneration (T. Sandhya et al., Brain Res., 788, 223-31 (1998)),inflammatory bowel disease, colitis, (I. Singer et al.,Gastroenterology, 115, 297-306 (1998)), cerebral ischemia (S. Nogawa etal., Proc. Natl. Acad. Sci., 95, 10966-71 (1998)), hypertension (A.Nasjletti, Hypertension, 31, 194-200 (1997)), among others.

[0005] Drugs that inhibit cyclooxygenase affect colon cancer (T.Kawamori et al., Cancer Res., 58, 409-12 (1998)), allergic neuritis (K.Miyamoto et al., Neuro Report, 9, 2331-4 (1998)), dementia, burninfections (M. Shoup, J. Trauma: Inj., Infec., Crit care, 45, 215-21(1998)), cytomegalovirus infectivity (E. Speir et al., Circ. Res., 83,210-16 (1998)), lumbago (H. Bosch, Curr. Med. Res. Opin., 14, 29-38(1997)), among others.

[0006] Japanese Patent No. 6166813 describes dihydrobenzopyrans asplastic additives. Japanese Patent No. 5032591 describes bicycliccompounds for preparing coloring materials. EP publication 736529,published Oct. 9, 1996, describes 2, 2-dimethyldihydrobenzopyrans asreagents for immunoassay. U.S. Pat. No. 5,773,203, issued Jun. 30, 1998,describes tetrahydroquinoline compounds for color imagining agents.Japanese patent 10069044 describes tetrahydroquinolines as color agents.Japanese patent 10062926 describes tetrahydroquinolines as color agents.Japanese patent 10062929 describes tetrahydroquinolines as color agents.U.S. Pat. No. 5,120,862, issued Jun. 9, 1992, describestetrahydronaphthalene carboxylic acids as intermediates. Japanesepublication 4009959 describes the use of dihydrothiobenzopyrans asphotographic agents. WO98/29386, published Jul. 9, 1998, describessulfonyl substituted dihydrobenzopyran derivatives as linkers. EP670312,published Sep. 6, 1995, describes tetrahydroquinolines as colordeveloping agents. WO98/12192 describes tetrahydroquinolines asherbicides. WO98/12180 describes tetrahydroquinolines as herbicides.

[0007] U.S. Pat. No. 4,954,518, issued Sep. 4, 1990, describesbenzopyran-ones for the treatment of inflammation. EP publication695547, published Feb, 7, 1996, describes benzopyran-ones asimmunomodulators. Japanese patent 6128155 describes antiinflammatorybenzopyranones. Japanese patent 5178745 describes antiinflammatorybenzopyranones. Japanese publication 6227971 describes amidinederivatives as antiviral agents. Japanese publication 8020532 describesamidine derivatives as pancreatitis agents. U.S. Pat. No. 5,639,911describes amidino compounds for the treatment of cancer. U.S. Pat. No.5,620,991 describes amidino compounds as factor Xa inhibitors. U.S. Pat.No. 5,462,965, issued Oct. 31, 1995, describes amino alcohols fortreatment of CNS disease. EP 363883 describes chroma-n derivatives forthe treatment of carrdiovascular disease. U.S. Pat. No. 4,777,257describes tetrahydronaphthyl acid derivatives for the inhibition ofthromboxane.

[0008] U.S. Pat. No. 5,731,324, issued Mar. 24, 1998, describesbenzopyran derivatives as platelet aggregation inhibitors. U.S. Pat. No.5,618,843 describes tetrahydronaphthalene derivatives as anti-plateletagents. PCT publication WO98/08836, published Mar. 5, 1998, describeschromene-3-carboxylic acid analogs as endothelin antagonists. PCTpublication WO95/04530, published Feb. 16, 1995, describestetrahydronaphthalene analogs as endothelin antagonists. PCT publicationWO98/38992, published Sep. 11, 1998, describes benzopyran analogs asremedies for peripheral circulation disturbances. U.S. Pat. No.5,112,972, issued May 12, 1992, describes chroman derivatives for thetreatment of cardiovascular disease. U.S. Pat. No. 5,387,587, issuedFeb. 7, 1995, describes chroman derivatives for the treatment ofcardiovascular disease. PCT publication WO96/15099, published May 23,1996, describes tetrahydronaphthalene carboxylic acid analogs asglutamate receptor agonist/antagonists. U.S. Pat. No. 5,124,325, issuedJun. 23, 1992, describes tetrahydroquinoline-8-carboxylic acidderivatives as agents to treat metabolic bone disease. Japanesepublication 9255660 describes the use of tetrahydoquinolines for thetreatment of vessel wall hypertrophy inhibitors. WO93/14066 describessulfonamide amino acid derivatives as CCK antagonists.

[0009] U.S. Pat. No. 4,889,871, issued Dec. 26, 1989, describesdihydrobenzopyran derivatives as leukotriene inhibitors. U.S. Pat. No.5,281,600, issued Jan. 25, 1994, describestetrahydroquinoline-8-carboxylic acid derivatives as antirheumatoidagents. WO93/15067 describes 4-hydroxy-dihydrobenzopyrans as LTB₄antagonists. U.S. Pat. No. 5,242,912, issued Sep. 7, 1993, describestetrahydroquinoline carboxylic acid derivatives as antirheumatoidagents. WO88/03805, published Jun. 2, 1988, describestetrahydronaphthalenes for the treatment of cancer. U.S. Pat. No.5,698,550 describes chroman derivatives as 5-lipoxygenase inhibitors.U.S. Pat. No. 5,552,441 describes leukotriene B4 antagonists.

[0010] The references below that disclose antiinflammatory activity,show continuing efforts to find a safe and effective antiinflammatoryagent. The novel dihydrobenzopyran, tetrahydroquinoline,dihydrobenzothiopyran and tetrahydronapthalene derivatives disclosedherein are such safe and also effective antiinflammatory agentsfurthering such efforts.

[0011] However, compounds of the current invention have not beendescribed as antiinflammatory cyclooxygenase-2 inhibitors.

DESCRIPTION OF THE INVENTION

[0012] A class of compounds useful in treating cyclooxygenase-2 mediateddisorders is defined by Formula I

[0013] wherein X is selected from O, S, CR^(c)R^(b) and NR^(a);

[0014] wherein R^(a) is selected from hydrido, C₁-C₃-alkyl,phenyl-C₁-C₃-alkyl, (substituted phenyl)-C₁-C₃-alkyl,C₁-C₃-alkoxycarbonyl-C₁-C₃-alkyl and carboxy-C₁-C₆-alkyl;

[0015] wherein each of R^(b) and R^(c) is independently selected fromhydrido, C₁-C₃-alkyl, substituted or unsubstituted phenyl-C₁-C₃-alkyl,C₁-C₃-perfluoroalkyl, chloro, C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro,cyano and cyano-C₁-C₃-alkyl; or wherein CR^(b)R^(c) forms a 3-6 memberedcycloalkyl ring;

[0016] wherein R is selected from carboxyl, aminocarbonyl,C₁-C₆-alkylsulfonylaminocarbonyl and C₁-C₆-alkoxycarbonyl;

[0017] wherein R″ is selected from hydrido, phenyl, thienyl, C₁-C₆-alkyland C₂-C₆-alkenyl;

[0018] wherein R¹ is selected from C₁-C₃-perfluoroalkyl, chloro,C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro, cyano and cyano-C₁-C₃-alkyl;

[0019] wherein R² is one or more radicals independently selected fromhydrido, halo, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,halo-C₂-C₆-alkynyl, aryl-C₁-C₃-alkyl, aryl-C₂-C₆-alkynyl,aryl-C₁-C₆-alkenyl, C₁-C₆-alkoxy, methylenedioxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, aryl-C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkoxy,aryl-C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,C₁-C₆-haloalkylthio, C₁-C₆-haloalkylsulfinyl, C₁-C₆-haloalkylsulfonyl,C₁-C₃-(haloalkyl)-C₁-C₃-hydroxyalkyl, C₁-C₆-hydroxyalkyl,hydroxyimino-C₁-C₆-alkyl, C₁-C₆-alkylamino, arylamino,N-aryl-N—C₁-C₆-alkylamino, heteroarylamino,N-heteroaryl-N—C₁-C₆-alkylamino, nitro, cyano, amino, aminosulfonyl,C₁-C₆-alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl,N-aryl-C₁-C₆-alkylaminosulfonyl, N-heteroaryl-C₁-C₆-alkylaminosulfonyl,heterocyclylsulfonyl, C₁-C₆-alkylsulfonyl, aryl-C₁-C₆-alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aryl-C₁-C₆-alkylcarbonyl, heteroaryl-C₁-C₆-alkylcarbonyl,heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C₁-C₆-alkoxycarbonyl,formyl, C₁-C₆-haloalkylcarbonyl and C₁-C₆-alkylcarbonyl; and

[0020] wherein the A ring atoms A¹, A², A³ and A⁴ are independentlyselected from carbon and nitrogen with the proviso that at least two ofA¹, A², A³ and A⁴ are carbon;

[0021] or wherein R² together with ring A forms a radical selected fromnaphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl anddibenzofuryl;

[0022] or an isomer or pharmaceutically acceptable salt thereof.

[0023] Compounds of the present invention would be useful for, but notlimited to, the treatment of inflammation in a subject, and fortreatment of other cyclooxygenase-2 mediated disorders, such as, as ananalgesic in the treatment of pain and headaches, or as an antipyreticfor the treatment of fever. For example, compounds of the inventionwould be useful to treat arthritis, including but not limited torheumatoid arthritis, spondyloarthropathies, gouty arthritis,osteoarthritis, systemic lupus erythematosus and juvenile arthritis.Such compounds of the invention would be useful in the treatment ofasthma, bronchitis, menstrual cramps, preterm labor, tendinitis,bursitis, allergic neuritis, cytomegalovirus infectivity, apoptosisincluding HIV induced apoptosis, lumbago, liver disease includinghepatitis, skin-related conditions such as psoriasis, eczema, acne, UVdamage, burns and dermatitis, and postoperative inflammation includingophthalmic surgery such as cataract surgery and refractive surgery.Compounds of the invention also would be useful to treatgastrointestinal conditions such as inflammatory bowel disease, Crohn'sdisease, gastritis, irritable bowel syndrome and ulcerative colitis.Compounds of the invention would be useful in treating inflammation insuch diseases as migraine headaches, periarteritis nodosa, thyroiditis,aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type Idiabetes, neuromuscular junction disease including myasthenia gravis,white matter disease including multiple sclerosis, sarcoidosis,nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis,nephritis, hypersensitivity, swelling occurring after injury includingbrain edema, myocardial ischemia, and the like. The compounds would alsobe useful in the treatment of ophthalmic diseases, such as retinitis,conjunctivitis, retinopathies, uveitis, ocular photophobia, and of acuteinjury to the eye tissue. The compounds would also be useful in thetreatment of pulmonary inflammation, such as that associated with viralinfections and cystic fibrosis, and in bone reorption such as associatedwith osteoporosis.

[0024] The compounds would also be useful for the treatment of certaincentral nervous system disorders, such as cortical dementias includingAlzheimer's disease, neurodegeneration, and central nervous systemdamage resulting from stroke, ischemia and trauma. The term “treatment”includes partial or total inhibition of the dementia, includingAlzheimer's disease, vascular dementia, multi-infarct dementia,pre-senile dementia, alcoholic dementia, and senile dementia.

[0025] The compounds of the invention are useful as antiinflammatoryagents, such as for the treatment of arthritis, with the additionalbenefit of having significantly less harmful side effects. Thesecompounds would also be useful in the treatment of allergic rhinitis,respiratory distress syndrome, endotoxin shock syndrome, and liverdisease. The compounds would also be useful in the treatment of pain,but not limited to postoperative pain, dental pain, muscular pain, andpain resulting from cancer.

[0026] The method above would be useful for, but not limited to,treating and preventing inflammation-related cardiovascular disorders ina subject. The method would be useful for treatment and prevention ofvascular diseases, coronary artery disease, aneurysm, vascularrejection, arteriosclerosis, atherosclerosis including cardiactransplant atherosclerosis, myocardial infarction, embolism, stroke,thrombosis, including venous thrombosis, angina including unstableangina, coronary plaque inflammation, bacterial-induced inflammationincluding Chlamydia-induced inflammation, viral induced inflammation,and inflammation associated with surgical procedures such as vasculargrafting including coronary artery bypass surgery, revascularizationprocedures including angioplasty, stent placement, endarterectomy, orother invasive procedures involving arteries, veins and capillaries.

[0027] The compounds would be useful for, but not limited to, thetreatment of angiogenesis-related disorders in a subject. According tothe present invention, the compounds can be administered to a subject inneed of angiogenesis inhibition. The method would be useful fortreatment of neoplasia, including metastasis; ophthalmologicalconditions such as corneal graft rejection, ocular neovascularization,retinal neovascularization including neovascularization following injuryor infection, diabetic retinopathy, macular degeneration, retrolentalfibroplasia and glaucoma; ulcerative diseases such as gastric ulcer;pathological, but non-malignant, conditions such as hemangiomas,including invantile hemaginomas, angiofibroma of the nasopharynx andavascular necrosis of bone; and disorders of the female reproductivesystem such as endometriosis.

[0028] Compounds of the invention would be useful for the prevention ortreatment of benign and malignant tumors/neoplasia including cancer,such as colorectal cancer, brain cancer, bone cancer, epithelialcell-derived neoplasia (epithelial carcinoma) such as basal cellcarcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer,mouth cancer, esophogeal cancer, siaall bowel cancer and stomach cancer,colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarycancer, cervical cancer, lung cancer, breast cancer and skin cancer,such as squamus cell and basal cell cancers, prostate cancer, renal cellcarcinoma, and other known cancers that effect epithelial cellsthroughout the body. Preferably, neoplasia is selected fromgastrointestinal cancer, Barrett's esophagus, liver cancer, bladdercancer, pancreas cancer, ovary cancer, prostate cancer, cervical cancer,lung cancer, breast cancer and skin cancer, such as squamus cell andbasal cell cancers. The compounds can also be used to treat the fibrosiswhich occurs with radiation therapy. The method can be used to treatsubjects having adenomatous polyps, including those with sporadicadenomatous polyposis (SAP) or familial adenomatous polyposis (FAP).Additionally, the method can be used to prevent polyps from forming inpatients at risk of FAP.

[0029] The administration of compounds of the present invention may beused alone or in conjunction with additional therapies known to thoseskilled in the art in the prevention or treatment of neoplasia.Alternatively, the compounds described herein may be used in conjunctivetherapy. By way of example, the compounds may be administered alone orin conjunction with other antineoplastic agents or other growthinhibiting agents or other drugs or nutrients.

[0030] There are large numbers of antineoplastic agents available incommercial use, in clinical evaluation and in pre-clinical development,which could be selected for treatment of neoplasia by combination drugchemotherapy. Such antineoplastic agents fall into several majorcategories, namely, antibiotic-type agents, alkylating agents,antimetabolite agents, hormonal agents, immunological agents,interferon-type agents and a category of miscellaneous agents.Alternatively, other anti-neoplastic agents, such as metallomatrixproteases (MMP), SOD mimics or α_(v)β₃ inhibitors may be used.

[0031] A first family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofantimetabolite-type antineoplastic agents. Suitable antimetaboliteantineoplastic agents may be selected from the group consisting of5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium,carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabinephosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,floxuridine, fludarabine phosphate, 5-fluorouracil,N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, TakedaTAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosinekinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT anduricytin.

[0032] A second family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofalkylating-type antineoplastic agents. Suitable alkylating-typeantineoplastic agents may be selected from the group consisting ofShionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone,Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102,carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil,cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233,cyplatate, Degussa D-19-384, Sumimoto DACHP (Myr)2,diphenylspiromustine, diplatinum cytostatic, Erba distamycinderivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517,estramustine phosphate sodium, fotemustine, Unimed G-6-M, ChinoinGYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide,mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215,oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine,semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus-tine,Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone,tetraplatin and trimelamol.

[0033] A third family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofantibiotic-type antineoplastic agents. Suitable antibiotic-typeantineoplastic agents may be selected from the group consisting of Taiho4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456,aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, NipponSoda anisomycins, anthracycline, azino-mycin-A, bisucaberin,Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551,Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-MyersBMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin,chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, KyowaHakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-Al, Kyowa HakkoDC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin,doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin,esperamicin-Al, esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK-973,fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin,herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, KyowaHakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa HakkoKT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji SeikaME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG,neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SR¹International NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin,pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin,rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, SnowBrand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SSPharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS PharmaceuticalSS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A,terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa HakkoUCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.

[0034] A fourth family of antineoplastic agents which may be used incombination with compounds of the present invention consists of amiscellaneous family of antineoplastic agents selected from the groupconsisting of alpha-carotene, alpha-difluoromethyl-arginine, acitretin,Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile,amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplastonA2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, HenkelAPD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin,benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene,Bristo-Myers BMY-40481, Vestar boron-10, bromofosfamide, WellcomeBW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride,Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100,Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941,Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICNcompound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm,cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate,dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether,dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, ToyoPharmar DM-75, Daiichi Seiyaku DN-9693, elliprabin, elliptinium acetate,Tsumura EPMTC, ergotamine, etoposide, etretinate, fenretinide, FujisawaFR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178,grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221,homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine,isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, KurehaChemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin,lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin,Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyaninederivatives, methylanilinoacridine, Molecular Genetics MGI-136,minactivin, mitonafide, mitoquidone, mopidamol, motretinide, ZenyakuKogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-LambertPD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptideD, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin,probimane, procarbazine, proglumide, Invitron protease nexin I, TobishiRA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine,retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976,SmithKline SK&F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharmSP-10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed,SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237,Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680,taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29,tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa HakkoUCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate,vincristine, vindesine, vinestramide, vinorelbine, vintriptol,vinzolidine, withanolides and Yamanouchi YM-534.

[0035] Examples of radioprotective agents which may be used incombination with compounds of the present invention are AD-5, adchnon,amifostine analogues, detox, dimesna, 1-102, MM-159,N-acylated-dehydroalanines, TGF— Genentech, tiprotimod, amifostine,WR-151327, FUT-187, ketoprofen transdermal, nabumetone, superoxidedismutase (Chiron) and superoxide dismutase Enzon.

[0036] Besides being useful for human treatment, these compounds arealso useful for veterinary treatment of companion animals, exoticanimals and farm animals, including mammals, rodents, and the like. Morepreferred animals include horses, dogs, and cats.

[0037] The present compounds may also be used in co-therapies, partiallyor completely, in addition to other antiinflammatories, such as togetherwith steroids, NSAIDs, iNOS inhibitors, p-38 inhibitors, TNF inhibitors,5-lipoxygenase inhibitors, LTB₄ receptor antagonists and LTA₄ hydrolaseinhibitors.

[0038] Suitable LTA₄ hydrolase inhibitors include RP-64966,(S,S)-3-amino-4-(4-benzyloxyphenyl)-2-hydroxybutyric acid benzyl ester(Scripps Res. Inst.),N-(2(R)-(cyclohexylmethyl)-3-(hydroxycarbamoyl)propionyl)-L-alanine(Searle), 7-(4-(4-ureidobenzyl)phenyl)heptanoic acid (Rhone-PoulencRorer), and 3-(3-(1E,3E-tetradecadienyl)-2-oxiranyl)benzoic acid lithiumsalt (Searle).

[0039] Suitable LTB₄ receptor antagonists include, among others,ebselen, linazolast, ontazolast, Bayer Bay-x-1005, Ciba Geigy compoundCGS-25019C, Leo Denmark compound ETH-615, Merck compound MAFP, Terumocompound. TMK-688, Tanabe compound T-0757, Lilly compounds LY-213024,LY-210073, LY223982, LY233469, and LY255283, LY-293111, 264086 and292728, ONO compounds ONO-LB457, ONO-4057, and ONO-LB-448, Shionogicompound S-2474, calcitrol, Lilly compounds Searle compounds SC-53228,SC-41930, SC-50605 and SC-51146, Warner Lambert compound BPC 15,SmithKline Beecham compound SB-209247 and SK&F compound SKF-104493.Preferably, the LTB₄ receptor antagonists are selected from calcitrol,ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmarkcompound ETH-615,. Lilly compound LY-293111, Ono compound ONO-4057, andTerumo compound TMK-688.

[0040] Suitable 5-LO inhibitors include, among others, Abbott compoundsA-76745, 78773 and ABT761, Bayer Bay-x-1005, Cytomed CMI-392, EisaiE-3040, Scotia Pharmaceutica EF-40, Fujirebio F-1322, Merckle ML-3000,Purdue Frederick PF-5901, 3M Pharmaceuticals R-840, rilopirox, flobufen,linasolast, lonapolene, masoprocol, ontasolast, tenidap, zileuton,pranlukast, tepoxalin, rilopirox, flezelastine hydrochloride, enazadremphosphate, and bunaprolast.

[0041] The present compounds may also be used in combination therapieswith opioids and other analgesics, including narcotic analgesics, Mureceptor antagonists, Kappa receptor antagonists, non-narcotic (i.e.non-addictive) analgesics, monoamine uptake inhibitors, adenosineregulating agents, cannabinoid derivatives, Substance P antagonists,neurokinin-1 receptor antagonists and sodium channel blockers, amongothers. More preferred would be combinations with compounds selectedfrom morphine, meperidine, codeine, pentazocine, buprenorphine,butorphanol, dezocine, meptazinol, hydrocodone, oxycodone, methadone,Tramadol [(+) enantiomer], DuP 747, Dynorphine A, Enadoline, RP-60180,HN-11608, E-2078, ICI-204448, acetominophen (paracetamol), propoxyphene,nalbuphine, E-4018, filenadol, mirfentanil, amitriptyline, DuP631,Tramadol [(−) enantiomer], GP-531, acadesine, AKI-1, AKI-2, GP-1683,GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742,SNX-111, ADL2-1294, ICI-204448, CT-3, CP-99,994, and CP-99,994.

[0042] The compounds can be used in co-therapies, in place of otherconventional antiinflammatories, in combination with one or moreantihistamines, decongestants, diuretics, antitussive agents or withother agents previously known to be effective in combination withantiinflammatory agents.

[0043] The term “prevention” includes either preventing the onset ofclinically evident cardiovascular disorders altogether or preventing theonset of a preclinically evident stage of cardiovascular disorder inindividuals. This includes prophylactic treatment of those at risk ofdeveloping a disease, such as a cardiovascular disorder, dementia orcancer, for example.

[0044] The phrase “therapeutically-effective” is intended to qualify theamount of each agent which will achieve the goal of improvement indisorder severity and the frequency of incidence over treatment of eachagent by itself, while avoiding adverse side effects typicallyassociated with alternative therapies.

[0045] The present invention preferably includes compounds whichselectively inhibit cyclooxygenase-2 over cyclooxygenase-1. Preferably,the compounds have a cyclooxygenase-2 IC₅₀ of less than about 0.5 μM,and also have a selectivity ratio of cyclooxygenase-2 inhibition overcyclooxygenase-1 inhibition of at least 50, and more preferably of atleast 100. Even more preferably, the compounds have a cyclooxygenase-1IC₅₀ of greater than about 5 μM. Such preferred selectivity may indicatean ability to reduce the incidence of common NSAID-induced side effects.

[0046] A preferred class of compounds consists of those compounds ofFormula I wherein X is selected from O, S, CR^(c)R^(b) and NR^(a);wherein R^(a) is selected from hydrido, C₁-C₃-alkyl, phenyl-C₁-C₃-alkyl,(substituted phenyl)-C₁-C₃-alkyl, C₁-C₃-alkoxycarbonyl-C₁-C₃-alkyl andcarboxy-C₁-C₆-alkyl; wherein each of R^(b) and R^(c) is independentlyselected from hydrido, C₁-C₃-alkyl, phenyl-C₁-C₃-alkyl, (substitutedphenyl)-C₁-C₃-alkyl, C₁-C₃-perfluoroalkyl, chloro, C₁-C₄-alkylthio,C₁-C₄-alkoxy, nitro, cyano and cyano-C₁-C₃-alkyl; or wherein CR^(b)R^(c)forms a cyclopropyl ring; wherein R is selected from carboxyl,aminocarbonyl, C₁-C₄-alkylsulfonylaminocarbonyl andC₁-C₄-alkoxycarbonyl; wherein R″ is selected from hydrido, phenyl,thienyl, C₁-C₄-alkyl and C₂-C₄-alkenyl; wherein R¹ is selected fromC₁-C₃-perfluoroalkyl, chloro, C₁-C₄-alkylthio, C₁-C₄-alkoxy, nitro,cyano and cyano-C₁-C₃-alkyl; wherein R² is one or more radicalsindependently selected from hydrido, halo, C₁-C₄-alkyl, C₂-C₄-alkenyl,C₂-C₆-alkynyl, halo-C₂-C₆-alkynyl, aryl-C₁-C₃-alkyl, aryl-C₂-C₄-alkynyl,aryl-C₂-C₄-alkenyl, C₁-C₄-alkoxy, methylenedioxy, C₁-C₄-alkylthio,C₁-C₄-alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy,C₁-C₄-alkoxy-C₁-C₄-alkyl, aryl-C₁-C₄-alkoxy, heteroaryl-C₁-C₄-alkoxy,aryl-C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy,C₁-C₄-haloalkylthio, C₁-C₄-haloalkylsulfinyl, C₁-C₄-haloalkylsulfonyl,C₁-C₃-(haloalkyl) —C₁-C₃-hydroxyalkyl, C₁-C₄-hydroxyalkyl,hydroxyimino-C₁-C₄-alkyl, C₁-C₄-alkylamino, arylamino,N-aryl-N—C₁-C₄-alkylamino, heteroarylamino,N-heteroaryl-N—C₁-C₄-alkylamino, nitro, cyano, amino, aminosulfonyl,C₁-C₄-alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl,aryl-C₁-C₄-alkylaminosulfonyl, heteroaryl-C₁-C₄-alkylaminosulfonyl,heterocyclylsulfonyl, C₁-C₄-alkylsulfonyl, aryl-C₁-C₄-alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aryl-C₁-C₄-alkylcarbonyl, heteroaryl-C₁-C₄-alkylcarbonyl,heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C₁-C₄-alkoxycarbonyl,formyl, C₁-C₄-haloalkylcarbonyl and C₁-C₄-alkylcarbonyl; and wherein theA ring atoms A¹, A², A³ and A₄ are independently selected from carbonand nitrogen with the proviso that at least three of A¹, A², A³ and A⁴are carbon; or wherein R² together with ring A forms a naphthyl orquinolyl radical; or an isomer or pharmaceutically acceptable saltthereof.

[0047] A more preferred class of compounds of Formula I consists ofcompounds wherein X is selected from O, S and NR^(a); wherein R^(a) isselected from hydrido, C₁-C₃-alkyl and (optionally substitutedphenyl)methyl; wherein R is carboxyl; wherein R″ is selected fromhydrido, C₁-C₃-alkyl and C₂-C₃-alkenyl; wherein R¹ is selected fromC₁-C₃-perfluoroalkyl; wherein R² is one or more radicals independentlyselected from hydrido, halo, C₁-C₄-alkyl, C₂-C₃-alkenyl, C₂-C₆-alkynyl,halo-C₂-C₆-alkynyl, optionally substituted phenyl-C₁-C₃-alkyl,optionally substituted phenyl-C₂-C₃-alkynyl, phenyl-C₂-C₃-alkenyl,C₁-C₃-alkoxy, methylenedioxy, C₁-C₃-alkoxy-C₁-C₃-alkyl, C₁-C₃-alkylthio,C₁-C₃-alkylsulfinyl, optionally substituted phenyloxy, optionallysubstituted phenylthio, optionally substituted phenylsulfinyl,C₁-C₃-haloalkyl-C₁-C₃-hydroxyalkyl, phenyl-C₁-C₃-alkoxy-C₁-C₃-alkyl,C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, C₁-C₃-haloalkylthio,C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy-C₁-C₃-alkyl, hydroxyimino-C₁-C₃-alkyl,C₁-C₆-alkylamino, nitro, cyano, amino, aminosulfonyl,N-alkylaminosulfonyl, N-arylaminosulfonyl, N-heteroarylaminosulfonyl,N-(phenyl-C₁-C₆-alkyl)aminosulfonyl,N-(heteroaryl-C₁-C₆-alkyl)aminosulfonyl, phenyl-C₁-C₃-alkylsulfonyl, 5-to 8-membered heterocyclylsulfonyl, C₁-C₃-alkylsulfonyl, optionallysubstituted phenyl, optionally substituted 5-to 9-membered heteroaryl,phenyl-C₁-C₃-alkylcarbonyl, phenylcarbonyl, 4-chlorophenylcarbonyl,4-hydroxyphenylcarbonyl, 4-trifluoromethylphenylcarbonyl,4-methoxyphenylcarbonyl, aminocarbonyl, formyl, and C₁-C₆-alkylcarbonyl;wherein the A ring atoms A¹, A², A³ and A⁴ are independently selectedfrom carbon and nitrogen with the proviso that at least three of A¹, A²,A³ and A⁴ are carbon; or wherein R² together with ring A forms anaphthyl, benzofurylphenyl, or quinolyl radical; or an isomer orpharmaceutically acceptable salt thereof.

[0048] An even more preferred class of compounds of Formula I consistsof compounds wherein X is selected from O, S and NR^(a); wherein R^(a)is selected from hydrido, methyl, ethyl, (4-trifluoromethyl)benzyl,(4-chloromethyl)benzyl, (4-methoxy)benzyl, (4-cyano)benzyl, and(4-nitro)benzyl; wherein R is carboxyl; wherein R″ is selected fromhydrido, ethyl and ethenyl; wherein R¹ is trifluoromethyl orpentafluoroethyl; wherein R² is one or more radicals independentlyselected from hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl,ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl,3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl,4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy,methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl,pentafluoroethyl, trifluoromethoxy, trifluoromethylthio, hydroxyinethyl,hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl,N-methylamino, nitro, cyano, amino, aminosulfonyl,N-methylaminosulfonyl, N-phenylaminosulfonyl, N-furylaminosulfonyl,N-(benzyl)aminosulfonyl, N-(furylmethyl)aminosulfonyl, benzylsulfonyl,phenylethylaminosulfonyl, furylsulfonyl, methylsulfonyl, phenyl, phenylsubstituted with one or more radicals selected from chloro, fluoro,bromo, methoxy, methylthio and methylsulfonyl, benzimidazolyl, thienyl,thienyl substituted with chloro, furyl, furyl substituted with chloro,benzylcarbonyl, optionally substituted phenylcarbonyl, aminocarbonyl,formyl and methylcarbonyl; wherein the A ring atoms A¹, A², A³ and A⁴are independently selected from carbon and nitrogen with the provisothat at least three of A¹, A², A³ and A⁴ are carbon; or wherein R²together with ring A forms a naphthyl, or quinolyl radical; or an isomeror pharmaceutically acceptable salt thereof.

[0049] Within Formula I there is a subclass of compounds of highinterest represented by Formula II

[0050] wherein R³ is selected from hydrido, C₁-C₃-alkyl,C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy and halo;

[0051] wherein R⁴ is selected from hydrido, halo, C₁-C₄-alkyl,C₁-C₃-alkylthio, C₁-C₃-haloalkyl, amino, aminosulfonyl,C₁-C₃-alkylsulfonyl, C₁-C₃-alkylsulfinyl, C₁-C₃-alkoxy-C₁-C₃-alkyl,C₁-C₃-alkylcarbonyl, formyl, cyano, C₁-C₃-haloalkylthio, substituted orunsubstituted phenylcarbonyl, C₁-C₃-haloalkoxy, C₁-C₃-alkoxy,aryl-C₁-C₃-alkylcarbonyl, di-C₁-C₃-alkylaminosulfonyl,C₁-C₃-alkylaminosulfonyl, aryl-C₁-C₃-alkylaminosulfonyl, 5- or6-heteroaryl-C₂-C₃-alkylaminosulfonyl, 5- or 6-membered heteroaryl,C₁-C₃-hydroxyalkyl, substituted or unsubstituted phenyl and 5- or6-membered nitrogen-containing heterocyclylsulfonyl;

[0052] wherein R⁵ is selected from hydrido, C₁-C₄-alkyl, halo,C₁-C₃-haloalkyl, C₁-C₄-hydroxyalkyl, C₂-C₃-alkynyl, C₂-C₃-alkenyl,C₁-C₃-alkoxy, phenoxy, phenoxy independently substituted with one ormore radicals selected from C₁-C₃-haloalkyl, nitro, carboxyl,C₁-C₃-haloalkoxy, C₁-C₃-alkoxy, cyano, C₁-C₃-alkyl and halo,naphthyloxy, naphthyloxy substituted with one or more halo radicals,phenylthio, phenylthio substituted with one or more halo radicals,phenylsulfinyl, phenylsulfinyl substituted with one or more haloradicals, phenylsulfonyl, phenylsulfonyl substituted with one or morehalo radicals, pyridinyloxy, pyridinyloxy substituted with one or morehalo radicals, and phenyl; and

[0053] wherein R⁶ is selected from hydrido, halo, cyano,hydroxyiminomethyl, C₁-C₃-hydroxyalkyl, C₁-C₃-alkynyl,phenyl-C₂-C₃-alkynyl, C₁-C₄-alkyl, C₁—. C₃-alkoxy, formyl and phenyl;

[0054] or an isomer or pharmaceutically acceptable salt thereof.

[0055] A class of compounds of particular interest consists of thosecompounds of Formula II wherein R³ is hydrido or chloro; wherein R⁴ isselected from hydrido, chloro, methyl, tert-butyl, methylthio,trifluoromethyl, difluoromethyl, pentafluoromethyl, trifluoromethylthio,trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl,and substituted or unsubstituted phenyl; wherein R⁵ is selected fromhydrido, methyl, tert-butyl, 2,2,2-trifluoroethoxy,2-hydroxy-1,1-dimethylethyl, phenoxy, 4-methoxyphenoxy, 4-chlorophenoxy,3-chlorophenoxy, 2-chlorophenoxy, 4-cyanophenoxy, 2,6-dimethylphenoxy,2,4-dichlorophenoxy, 3,4-difluorophenoxy, 4-chloro-3-fluorophenoxy,4-(trifluoromethyl)phenoxy, 4-nitrophenoxy, 4-carboxyphenoxy,3-carboxyphenoxy, 2-chloro-4-carboxyphenoxy,4-(trifluoromethoxy)phenoxy, 2-bromo-4-chlorophenoxy,(6-bromo-2-naphthalenyl)oxy, phenylthio, (4-methoxyphenyl)thio,(4-chlorophenyl)thio, (4-chlorophenyl)sulfinyl,(4-chlorophenyl)sulfonyl, (6-chloro-2-pyridinyl)oxy,(2-chloro-3-pyridinyl)oxy, (3-pyridinyl)oxy, (2-pyridinyl)oxy, iodo,ethenyl, ethynyl, chloro; and wherein R⁶ is selected from hydrido,chloro, thienyl, hydroxyiminomethyl, substituted or unsubstitutedphenylethynyl, phenyl and substituted phenyl; or an isomer orpharmaceutically acceptable salt thereof.

[0056] Within Formula I there is a subclass of compounds of highinterest represented by Formula III:

[0057] wherein R^(a) is selected from hydrido and lower aralkyl;

[0058] wherein R³ is selected from hydrido, C₁-C₃-alkyl,C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy and halo;

[0059] wherein R⁴ is selected from hydrido, halo, C₁-C₄-alkyl,C₁-C₃-alkylthio, C₁-C₃-haloalkyl, amino, aminosulfonyl,C₁-C₃-alkylsulfonyl, C₁-C₃-alkylsulfinyl, C₁-C₃-alkoxy-C₁-C₃-alkyl,C₁-C₃-alkylcarbonyl, formyl, cyano, C₁-C₃-haloalkylthio, substituted orunsubstituted phenylcarbonyl, C₁-C₃-haloalkoxy, C₁-C₃-alkoxy,aryl-C₁-C₃-alkylcarbonyl, di-C₁-C₃-alkylaminosulfonyl,C₁-C₃-alkylaminosulfonyl, aryl-C₁-C₃-alkylaminosulfonyl, 5- or6-heteroaryl-C₁-C₃-alkylaminosulfonyl, 5- or 6-membered heteroaryl,C₁-C₃-hydroxyalkyl, substituted or unsubstituted phenyl and 5- or6-membered nitrogen-containing heterocyclylsulfonyl;

[0060] wherein R⁵ is selected from hydrido, C₁-C₄-alkyl, halo,C₁-C₃-haloalkyl, C₁-C₄-hydroxyalkyl, C₂-C₃-alkynyl, C₂-C₃-alkenyl,C₁-C₃-alkoxy, phenoxy, phenoxy independently substituted with one ormore radicals selected from C₁-C₃-haloalkyl, nitro, carboxyl,C₁-C₃-haloalkoxy, C₁-C₃-alkoxy, cyano, C₁-C₃-alkyl and halo,naphthyloxy, naphthyloxy substituted with one or more halo radicals,phenylthio, phenylthio substituted with one or more halo radicals,phenylsulfinyl, phenylsulfinyl substituted with one or more haloradicals, phenylsulfonyl, phenylsulfonyl substituted with one or morehalo radicals, pyridinyloxy, pyridinyloxy substituted with one or morehalo radicals, and phenyl; and

[0061] wherein R⁶ is selected from hydrido, halo, cyano,hydroxyiminomethyl, C₁-C₃-hydroxyalkyl, C₂-C₃-alkynyl,phenyl-C₂-C₃-alkynyl, C₁-C₄-alkyl, C₁-C₃-alkoxy, formyl and phenyl; oran isomer or pharmaceutically acceptable salt thereof.

[0062] A class of compounds of particular interest consists of thosecompounds of Formula III R³ is hydrido or chloro; wherein R⁴ is selectedfrom hydrido, chloro, methyl, tert-butyl, methylthio, trifluoromethyl,difluoromethyl, pentafluoromethyl, trifluoromethylthio,trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl,and substituted or unsubstituted phenyl; wherein R⁵ is selected fromhydrido, methyl, tert-butyl, 2,2,2-trifluoroethoxy,2-hydroxy-1,1-dimethylethyl, phenoxy, 4-methoxyphenoxy, 4-chlorophenoxy,3-chlorophenoxy, 2-chlorophenoxy, 4-cyanophenoxy, 2,6-dimethylphenoxy,2,4-dichlorophenoxy, 3,4-difluorophenoxy, 4-chloro-3-fluorophenoxy,4-(trifluoromethyl)phenoxy, 4-nitrophenoxy, 4-carboxyphenoxy,3-carboxyphenoxy, 2-chloro-4-carboxyphenoxy,4-(trifluoromethoxy)phenoxy, 2-bromo-4-chlorophenoxy,(6-bromo-2-naphthalenyl)oxy, phenylthio, (4-methoxyphenyl)thio,(4-chlorophenyl)thio, (4-chlorophenyl)sulfinyl,(4-chlorophenyl)sulfonyl, (6-chloro-2-pyridinyl)oxy,(2-chloro-3-pyridinyl)oxy, (3-pyridinyl)oxy, (2-pyridinyl)oxy, iodo,ethenyl, ethynyl, chloro; and wherein R is selected from hydrido,chloro, thienyl, hydroxyiminomethyl, substituted or unsubstitutedphenylethynyl, phenyl and substituted phenyl; or an isomer orpharmaceutically acceptable salt thereof.

[0063] Within Formula I there is a subclass of compounds of highinterest represented by Formula IV

[0064] wherein R³ is selected from hydrido, C₁-C₃-alkyl,C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy and halo;

[0065] wherein R⁴ is selected from hydrido, halo, C₁-C₄-alkyl,C₁-C₃-alkylthio, C₁-C₃-haloalkyl, amino, aminosulfonyl,C₁-C₃-alkylsulfonyl, C₁-C₃-alkylsulfinyl, C₁-C₃-alkoxy-C₁-C₃-alkyl,C₁-C₃-alkylcarbonyl, formyl, cyano, C₁-C₃-haloalkylthio, substituted orunsubstituted phenylcarbonyl, C₁-C₃-haloalkoxy, C₁-C₃-alkoxy,aryl-C₁-C₃-alkylcarbonyl, di-C₁-C₃-alkylaminosulfonyl,C₁-C₃-alkylaminosulfonyl, aryl-C₁-C₃-alkylaminosulfonyl, 5- or6-heteroaryl-C₁-C₃-alkylaminosulfonyl, 5- or 6-membered heteroaryl,C₁-C₃-hydroxyalkyl, substituted or unsubstituted phenyl and 5- or6-membered nitrogen-containing heterocyclylsulfonyl;

[0066] wherein R⁵ is selected from hydrido, C₁-C₄-alkyl, halo,C₁-C₃-haloalkyl, C₁-C₄-hydroxyalkyl, C₂-C₃-alkynyl, C₂-C₃-alkenyl,C₁-C₃-alkoxy, phenoxy, phenoxy independently substituted with one ormore radicals selected from C₁-C₃-haloalkyl, nitro, carboxyl,C₁-C₃-haloalkoxy, C₁-C₃-alkoxy, cyano, C₁-C₃-alkyl and halo,naphthyloxy, naphthyloxy substituted with one or more halo radicals,phenylthio, phenylthio substituted with one or more halo radicals,phenylsulfinyl, phenylsulfinyl substituted with one or more haloradicals, phenylsulfonyl, phenylsulfonyl substituted with one or morehalo radicals, pyridinyloxy, pyridinyloxy substituted with one or morehalo radicals, and phenyl; and

[0067] wherein R⁶ is selected from hydrido, halo, cyano,hydroxyiminomethyl, C₁-C₃-hydroxyalkyl, C₂-C₃-alkynyl,phenyl-C₂-C₃-alkynyl, C₁-C₄-alkyl, C₁-C₃-alkoxy, formyl and phenyl; oran isomer or pharmaceutically acceptable salt thereof.

[0068] A class of compounds of particular interest consists of thosecompounds of Formula IV R³ is hydrido or chloro; wherein R⁴ is selectedfrom hydrido, chloro, methyl, tert-butyl, methylthio, trifluoromethyl,difluoromethyl, pentafluoromethyl, trifluoromethylthio,trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl,and substituted or unsubstituted phenyl; wherein R⁵ is selected fromhydrido, methyl, tert-butyl, 2,2,2-trifluoroethoxy,2-hydroxy-1,1-dimethylethyl, phenoxy, 4-methoxyphenoxy, 4-chlorophenoxy,3-chlorophenoxy, 2-chlorophenoxy, 4-cyanophenoxy, 2,6-dimethylphenoxy,2,4-dichlorophenoxy, 3,4-difluorophenoxy, 4-chloro-3-fluorophenoxy,4-(trifluoromethyl)phenoxy, 4-nitrophenoxy, 4-carboxyphenoxy,3-carboxyphenoxy, 2-chloro-4-carboxyphenoxy,4-(trifluoromethoxy)phenoxy, 2-bromo-4-chlorophenoxy,(6-bromo-2-naphthalenyl)oxy, phenylthio, (4-methoxyphenyl)thio,(4-chlorophenyl)thio, (4-chlorophenyl)sulfinyl,(4-chlorophenyl)sulfonyl, (6-chloro-2-pyridinyl)oxy,(2-chloro-3-pyridinyl)oxy, (3-pyridinyl)oxy, (2-pyridinyl)oxy, iodo,ethenyl, ethynyl, chloro; and wherein R⁶ is selected from hydrido,chloro, thienyl, hydroxyiminomethyl, substituted or unsubstitutedphenylethynyl, phenyl and substituted phenyl; or an isomer orpharmaceutically acceptable salt thereof.

[0069] A family of specific compounds of particular interest withinFormula I consists of compounds and pharmaceutically-acceptable saltsthereof as follows:

[0070]6-chloro-3,4-dihydro-7-[(2-pyridyl-N-oxide)thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0071]6-chloro-3,4-dihydro-7-[(3-chloro-2-pyridyl-{N-oxide})thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0072] 6-chloro-1,2,3,4-tetrahydro-7-[(2-pyridyl-N-oxide)oxy]-2-(trifluoromethyl)-2H-quinoline-3-carboxylic acid;

[0073] 6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})oxy]-1,2,3,4-tetrahydro-2-(trifluoromethyl)-2H-quinoline-3-carboxylicacid;

[0074] 6-chloro-1,2,3,4-tetrahydro-7-[(2-pyridyl-N-oxide)thio]-2-(trifluoromethyl)-2H-quinoline-3-carboxylic acid;

[0075] 6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})thio]-1,2,3,4-tetrahydro-2-(trifluoromethyl)-2H-quinoline-3-carboxylicacid;

[0076]6-chloro-3,4-dihydro-7-[(2-pyridyl-N-oxide)oxy]-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0077] 6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0078]6-chloro-3,4-dihydro-7-[(2-pyridyl-N-oxide)thio]-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0079]6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})thio]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0080]6-chloro-7-(3,4-dichlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0081]6-chloro-7-(3-bromo-4-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0082]6-chloro-7-(4-bromo-3-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0083]6-chloro-7-(3,4-dibromophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0084]6-chloro-7-[4-chloro-3-(trifluoromethyl)phenoxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0085]6-chloro-7-[3-chloro-4-(trifluoromethyl)phenoxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0086]6-chloro-7-(2,6-dichlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0087]6-chloro-7-(2,6-dibromophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0088]6-chloro-7-(2,6-difluorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0089]6-chloro-7-(2,5-dichlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0090]6-chloro-7-(2,5-dibromophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0091]6-chloro-7-(2,5-difluorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0092]6-chloro-7-(2,3-dichlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0093]6-chloro-7-(2,3-dibromophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0094]6-chloro-7-(2,3-difluorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0095]6-chloro-7-(4-chloro-3-cyanophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0096]6-chloro-3,4-dihydro-7-(3-tert-butylphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0097]6-chloro-3,4-dihydro-7-(2-tert-butylphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0098]6-chloro-7-(4-chloro-3-tert-butylphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0099]6-chloro-7-(4-chloro-2-tert-butylphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0100] 6-chloro-7-(2-chloro-3-tert-butylphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0101]3,4-dihydro-7-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0102]6-chloro-3,4-dihydro-7-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0103]6-chloro-3,4-dihydro-7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0104]3,4-dihydro-7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic;

[0105]6-chloro-3,4-dihydro-7-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0106]6-chloro-3,4-dihydro-7-ethynyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0107]6-chloro-3,4-dihydro-7-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0108]6-chloro-3,4-dihydro-7-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0109]6-chloro-7-(4-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0110]6-chloro-7-(4-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0111]6-chloro-7-(4-cyanophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0112] 6-chloro-3,4-dihydro-7-[4-(trifluoromethyl)phenoxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0113]6-chloro-3,4-dihydro-7-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0114]6-chloro-7-(2-bromo-4-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0115]6-chloro-7-[(6-bromo-2-naphthyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0116]6-chloro-3,4-dihydro-7-(2,6-dimethylphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0117]6-chloro-3,4-dihydro-7-[(4-methoxyphenyl)thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0118]6-chloro-7-[(4-chlorophenyl)thio]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0119]6-chloro-7-[(4-chlorophenyl)sulfinyl]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0120]6-chloro-7-[(4-chlorophenyl)sulfonyl]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0121]6-chloro-3,4-dihydro-7-phenylthio-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0122]6-chloro-7-(3-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0123]6-chloro-7-(2,4-dichlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0124]6-chloro-7-(3,4-difluorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0125]6-chloro-7-[(6-chloro-2-pyridinyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0126]6-chloro-7-[(2-chloro-3-pyridinyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0127]6-chloro-3,4-dihydro-7-[(3-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0128]6-chloro-3,4-dihydro-7-[(2-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0129]6-chloro-3,4-dihydro-7-(4-nitrophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0130]6-chloro-7-(2-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0131]6-chloro-7-(4-chloro-3-fluorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0132]6-chloro-7-(4-carboxyphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0133]6-chloro-7-(2-chloro-4-carboxyphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0134]6-chloro-7-(3-carboxyphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0135]6-chloro-3,4-dihydro-7-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0136]6-chloro-1,2,3,4-tetrahydro-8-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0137]1,2,3,4-tetrahydro-5-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0138]1,2,3,4-tetrahydro-6-(4-fluorophenyl)-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0139]1,2,3,4-tetrahydro-6-ethynyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0140]8-bromo-1,2,3,4-tetrahydro-6-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0141]1,2,3,4-tetrahydro-6-phenylethynyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0142]6-chloro-3,4-dihydro-7-[(3-pyridyl-N-oxide)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0143]6-chloro-3,4-dihydro-7-[(2-pyridyl-N-oxide)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0144] 6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0145] 6-chloro-7-[(4-chloro-2-pyridyl-{N-oxide})oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0146]6-chloro-7-[(5-chloro-2-pyridyl-{N-oxide})oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0147]6-chloro-7-[(6-chloro-2-pyridyl-{N-oxide})oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0148]6-chloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0149]3,4-dihydro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0150]7-methyl-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0151] 2,7-bis(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-3-carboxylicacid;

[0152]7-bromo-3,4-dihydro-2-trifluoromethy1-2H-1-benzopyran-3-carboxylic acid;

[0153]6-chloro-3,4-dihydro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0154]3,4-dihydro-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0155]6-chloro-3,4-dihydro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0156]6-chloro-3,4-dihydro-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0157] 3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0158]3,4-dihydro-8-ethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0159]3,4-dihydro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0160]6-bromo-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0161]8-chloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0162]8-bromo-6-chloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0163]3,4-dihydro-6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0164]3,4-dihydro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0165]5,7-dichloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0166]7,8-dichloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0167]3,4-dihydro-7-isopropyloxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0168]3,4-dihydro-8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0169]3,4-dihydro-7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0170]6,8-bis(1,1-dimethylethyl)-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0171]7-chloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0172]3,4-dihydro-7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0173]3,4-dihydro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0174]6-chloro-3,4-dihydro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0175]3,4-dihydro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0176]6-chloro-3,4-dihydro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0177]6-chloro-3,4-dihydro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0178]6,7-dichloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0179]6,8-dichloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0180]6,8-dibromo-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0181]3,4-dihydro-6,8-dimethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0182]3,4-dihydro-6-nitro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0183]6-amino-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;ethyl6-amino-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate;

[0184]6-chloro-3,4-dihydro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0185]8-chloro-3,4-dihydro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0186]8-chloro-3,4-dihydro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0187]6,8-difluoro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0188]6-bromo-8-chloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0189]8-bromo-3,4-dihydro-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0190]8-bromo-3,4-dihydro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0191]8-bromo-3,4-dihydro-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0192]6-chloro-3,4-dihydro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0193]6-bromo-3,4-dihydro-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0194]7-(N,N-diethylamino)-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0195]3,4-dihydro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0196]3,4-dihydro-6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0197]6-aminosulfonyl-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0198]3,4-dihydro-6-(methylamino)sulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0199]3,4-dihydro-6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0200]3,4-dihydro-6-[(1,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0201]3,4-dihydro-6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0202]3,4-dihydro-6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0203]8-chloro-3,4-dihydro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0204]6-N,N-diethylaminosulfonyl-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0205]3,4-dihydro-6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0206]3,4-dihydro-6-(2,2-dimethylpropylcarbonyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0207]6,8-dichloro-3,4-dihydro-7-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0208]6-chloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylicacid;

[0209]3,4-dihydro-6-[[(2-furanylmethyl)amino]sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0210]3,4-dihydro-6-[(phenylmethyl)sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0211]3,4-dihydro-6-[[(phenylethyl)amino]sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0212] 3,4-dihydro-6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0213]6-chloro-3,4-dihydro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0214]8-bromo-6-chloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0215]3,4-dihydro-6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0216]6-chloro-3,4-dihydro-8-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0217]6-bromo-7-(1,1-dimethylethyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0218]5,6-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0219]6-cyano-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0220]3,4-dihydro-6-hydroxymethyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0221]6-(difluoromethyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0222] 2,6-bis(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-3-carboxylicacid;

[0223]3,4-dihydro-5,6,7-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0224]3,4-dihydro-6,7,8-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0225]3,4-dihydro-6-(methylthio)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0226]3,4-dihydro-6-(methylsulfinyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0227]5,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0228]3,4-dihydro-6-(pentafluoroethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0229]3,4-dihydro-6-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0230]3,4-dihydro-2-(trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzopyran-3-carboxylicacid;

[0231]6,8-dichloro-3,4-dihydro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0232]6-chloro-2,7-bis(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-3-carboxylicacid;

[0233]3,4-dihydro-5-methoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0234]6-benzoyl-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0235]6-(4-chlorobenzoyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0236]3,4-dihydro-6-(4-hydroxybenzoyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0237] 3,4-dihydro-6-phenoxy-2-(trifluoromethyl)-2μl-1-benzopyran-3-carboxylic acid;

[0238]8-chloro-6-(4-chlorophenoxy)-3,4-dihydro-2-trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0239]3,4-dihydro-2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy)-2H-1-benzopyran-3-carboxylicacid;

[0240]3,4-dihydro-6-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0241]6-(3-chloro-4-methoxyphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0242]6-(4-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0243]8-chloro-3,4-dihydro-2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenoxy]-2H-1-benzopyran-3-carboxylicacid;

[0244]6-chloro-8-cyano-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0245]6-chloro-3,4-dihydro-8-[(hydroxyimino)methyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0246]6-chloro-8-(hydroxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0247]8-(1H-benzimidazol-2-yl)-6-chloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0248]3,4-dihydro-7-(1,1-dimethylethyl)-2-(pentafluoroethyl)-2H-1-benzopyran-3-carboxylicacid;

[0249]6-chloro-3,4-dihydro-8-(methoxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0250]6-chloro-8-(benzyloxymethyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0251]6-chloro-3,4-dihydro-8-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0252]6-chloro-3,4-dihydro-8-ethynyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0253]6-chloro-3,4-dihydro-8-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0254]6-chloro-3,4-dihydro-8-(2-furanyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0255]6-chloro-8-(5-chloro-1-pentynyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0256]6-chloro-3,4-dihydro-8-(1-pentynyl)-2-(trifluoroinethyl)-2H-1-benzopyran-3-carboxylicacid;

[0257]6-chloro-3,4-dihydro-8-(phenylethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0258]6-chloro-3,4-dihydro-8-(3,3-dimethyl-1-butynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0259]6-chloro-8-[(4-chlorophenyl)ethynyl]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0260]6-chloro-3,4-dihydro-8-[(4-methoxyphenyl)ethynyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0261]3,4-dihydro-6-(phenylethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0262]6-chloro-8-(4-chlorophenyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0263]6-chloro-3,4-dihydro-8-(3-methoxyphenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0264]6-chloro-3,4-dihydro-8-[(4-methylthio)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0265]6-chloro-3,4-dihydro-8-[(4-methylsulfonyl)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0266]6-chloro-3,4-dihydro-8-phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0267]6-bromo-3,4-dihydro-8-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0268]3,4-dihydro-6-(4-fluorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0269]3,4-dihydro-6-phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0270]8-chloro-3,4-dihydro-6-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0271]3,4-dihydro-6,8-diiodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0272]6-(5-chloro-2-thienyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0273]3,4-dihydro-6-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0274]6-(4-chlorophenyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0275]6-(4-bromophenyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0276]3,4-dihydro-6-(ethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0277]3,4-dihydro-6-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0278]6-chloro-3,4-dihydro-8-(4-methoxyphenyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0279]6-chloro-3,4-dihydro-2-(trifluoromethyl)-4-ethenyl-2H-1-benzopyran-3-carboxylicacid;

[0280]6-chloro-3,4-dihydro-2-(trifluoromethyl)-4-phenyl-2H-1-benzopyran-3-carboxylicacid;

[0281]6-chloro-3,4-dihydro-4-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0282]3,4-dihydro-6-(2,2,2-trifluoro-1-hydroxyethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0283]3,4-dihydro-6-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0284]3,4-dihydro-6,8-dimethyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0285]3,4-dihydro-6-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0286]3,4-dihydro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0287]3,4-dihydro-6,7-dimethyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0288]3,4-dihydro-8-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0289] 3,4-dihydro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0290]6-chloro-3,4-dihydro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0291]7-chloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0292]6,7-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0293]3,4-dihydro-2-(trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzothiopyran-3-carboxylicacid;

[0294]6,8-dichloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylicacid;

[0295]6-chloro-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0296]6,8-dichloro-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0297]6,7-difluoro-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0298]6-iodo-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0299]6-bromo-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0300]1,2,3,4-tetrahydro-6-(trifluoromethoxy)-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0301]6-(trifluoromethyl)-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0302]6-cyano-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0303]6-chloro-1,2,3,4-tetrahydro-1-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0304]6-chloro-1,2,3,4-tetrahydro-2-(trifluoromethyl)-1-[[4-(trifluoromethyl)phenyl]methyl]-3-3-quinolinecarboxylicacid;

[0305]6-chloro-1-[(4-chlorophenyl)methyl]-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0306]6-chloro-1,2,3,4-tetrahydro-2-(trifluoromethyl)-1-[[4-(methoxy)phenyl]methyl]-3-quinolinecarboxylicacid;

[0307]6-chloro-1-[(4-cyanophenyl)methyl]-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0308]6-chloro-1,2,3,4-tetrahydro-1-[(4-nitrophenyl)methyl]-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0309]6-chloro-1,2,3,4-tetrahydro-1-ethyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0310]6-chloro-2-(triflouromethyl)-1,2,3,4-tetrahydro[1,8]napthyridine-3-carboxylicacid;

[0311]6-chloro-3,4-dihydro-7-[(3-pyridyl-N-oxide)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[0312]6-chloro-3,4-dihydro-7-[(2-pyridyl-N-oxide)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0313]6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0314]6-chloro-7-[(4-chloro-2-pyridyl-{N-oxide})oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0315]6-chloro-7-[(5-chloro-2-pyridyl-{N-oxide})oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0316]6-chloro-7-[(6-chloro-2-pyridyl-{N-oxide})oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0317]6-chloro-3,4-dihydro-7-[(2-pyridyl-N-oxide)thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0318]6-chloro-7-[(3-chloro-2-pyridyl-{N-oxidel)thio]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0319]6-chloro-7-[(2-pyridyl-N-oxide)oxy]-2-(trifluoromethyl)-2H-12,3,4-tetrahydroquinoline-3-carboxylicacid;

[0320]6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})oxy]-2-(trifluoromethyl)-2H-1,2,3,4-tetrahydroquinoline-3-carboxylicacid;

[0321] 6-chloro-7-[(2-pyridyl-N-oxide)thio]-2-(trifluoromethyl)-2H-12,3,4-tetrahydroquinoline-3-carboxylicacid;

[0322]6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})thio]-2-(trifluoromethyl)-2H-1,2,3,4-tetrahydroquinoline-3-carboxylicacid;

[0323]6-chloro-3,4-dihydro-7-[(2-pyridyl-N-oxide)oxy]-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0324]6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0325]6-chloro-3,4-dihydro-7-[(2-pyridyl-N-oxide)thio]-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0326]6-chloro-7-[(3-chloro-2-pyridyl-1N-oxide})thio]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0327]3,4-dihydro-7-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0328]6-chloro-3,4-dihydro-7-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0329]6-chloro-3,4-dihydro-7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0330]3,4-dihydro-7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic;

[0331]6-chloro-3,4-dihydro-7-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0332]6-chloro-3,4-dihydro-7-ethynyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0333]6-chloro-3,4-dihydro-7-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0334]6-chloro-3,4-dihydro-7-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0335]6-chloro-7-(4-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0336]6-chloro-7-(4-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0337]6-chloro-7-(4-cyanophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0338]6-chloro-3,4-dihydro-7-[4-(trifluoromethyl)phenoxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0339]6-chloro-3,4-dihydro-7-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0340]6-chloro-7-(2-bromo-4-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0341]6-chloro-7-[(6-bromo-2-naphthyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0342]6-chloro-3,4-dihydro-7-(2,6-dimethylphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0343]6-chloro-3,4-dihydro-7-[(4-methoxyphenyl)thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0344]6-chloro-7-[(4-chlorophenyl)thio]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0345]6-chloro-7-[(4-chlorophenyl)sulfinyl]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0346]6-chloro-7-[(4-chlorophenyl)sulfonyl]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0347]6-chloro-3,4-dihydro-7-phenylthio-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0348]6-chloro-7-(3-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0349]6-chloro-7-(2,4-dichlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0350]6-chloro-7-(3,4-difluorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0351]6-chloro-7-[(6-chloro-2-pyridinyl)oxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0352]6-chloro-7-[(2-chloro-3-pyridinyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0353]6-chloro-3,4-dihydro-7-[(3-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0354]6-chloro-3,4-dihydro-7-[(2-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0355]6-chloro-3,4-dihydro-7-(4-nitrophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0356]6-chloro-7-(2-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0357]6-chloro-7-(4-chloro-3-fluorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0358]6-chloro-7-(4-carboxyphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0359]6-chloro-7-(2-chloro-4-carboxyphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0360]6-chloro-7-(3-carboxyphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0361]6-chloro-3,4-dihydro-7-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0362]1,2,3,4-tetrahydro-6-ethynyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0363]1,2,3,4-tetrahydro-6-phenylethynyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0364]6-chloro-7-(3,4-dichlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0365]6-chloro-7-(3-bromo-4-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0366]6-chloro-7-(4-bromo-3-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0367]6-chloro-7-(3,4-dibromophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0368]6-chloro-7-[4-chloro-3-(trifluoromethyl)phenoxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0369]6-chloro-7-(3-chloro-4-(trifluoromethyl)phenoxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0370]6-chloro-7-(2,6-dichlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0371]6-chloro-7-(2,6-dibromophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0372]6-chloro-7-(2,6-difluorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0373]6-chloro-7-(2,5-dichlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0374]6-chloro-7-(2,5-dibromophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0375]6-chloro-7-(2,5-difluorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0376]6-chloro-7-(2,3-dichlorophenoxy)-v2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0377]6-chloro-7-(2,3-dibromophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0378]6-chloro-7-(2,3-difluorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0379]6-chloro-7-(4-chloro-3-cyanophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0380]6-chloro-3,4-dihydro-7-(3-tert-butylphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0381]6-chloro-3,4-dihydro-7-(2-tert-butylphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0382]6-chloro-7-(4-chloro-3-tert-butylphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0383]6-chloro-7-(4-chloro-2-tert-butylphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0384] 6-chloro-7-(2-chloro-3-tert-butylphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0385] 6-chloro-7-(3-chloro-2-tert-butylphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0386]6-chloro-3,4-dihydro-7-(3-thienyloxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0387]6-chloro-7-(2-chloro-3-thienyloxy)-3,4-dihydro-2.-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0388]6-chloro-7-(4-chloro-3-thienyloxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0389]6-chloro-7-(5-chloro-3-thienyloxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0390]6-chloro-7-(2,5-dichloro-3-thienyloxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0391]6-chloro-7-(2,4-dichloro-3-thienyloxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0392]6-chloro-7-[(3-chloro-2-pyridyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0393]6-chloro-7-[(4-chloro-2-pyridyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0394]6-chloro-7-[(3-chloro-2-pyridyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0395]6-chloro-7-[(5-chloro-2-pyridyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0396]6-chloro-7-[(6-chloro-2-pyridyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0397]6-chloro-7-[(5,6-dichloro-2-pyridyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0398]6-chloro-7-[(3,4-dichloro-2-pyridyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0399]6-chloro-7-[(4,5-dichloro-2-pyridyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0400]6-chloro-7-[(3,5-dichloro-2-pyridyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0401]6-chloro-7-[(3,6-dichloro-2-pyridyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0402]6-chloro-7-[(4,5-dichloro-2-pyridyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0403]6-chloro-7-[(4,6-dichloro-2-pyridyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0404]6-chloro-7-[(5,6-dichloro-2-pyridyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0405]6-chloro-3,4-dihydro-7-[(2-quinolyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0406] 3,4-dihydro-2-trifluoromethyl-2H-naphtho[1,2-b]pyran-3-carboxylicacid;

[0407] 3,4-dihydro-2-trifluoromethyl-3H-naphtho[2,1-b]pyran-3-carboxylicacid;

[0408] 3,4-dihydro-2-trifluoromethyl-2H-naphtho[2,3-b]pyran-3-carboxylicacid;

[0409]3,4-dihydro-5-(hydroxymethyl)-8-methyl-2-(trifluoromethyl)-2H-pyrano[2,3-c]pyridine-3-carboxylicacid;

[0410]3,4-dihydro-6-(trifluoromethyl)-6H-1,3-dioxolo[4,5-g][l]benzopyran-7-carboxylicacid; and

[0411] 3,4-dihydro-3-(trifluoromethyl)-3H-benzofuro[3,2-f][1]benzopyran-2-carboxylic acid.

[0412] A preferred family of specific compounds of particular interestwithin Formulas I-I″ consists of compounds as follows:

[0413](2S,3R)-3,4-dihydro-7-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0414] (2S,3R)-6-chloro-3,4-dihydro-7-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0415](2S,3R)-6-chloro-3,4-dihydro-7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0416](2S,3R)-3,4-dihydro-7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic;(2S,3R)-6-chloro-3,4-dihydro-7-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0417](2S,3R)-6-chloro-3,4-dihydro-7-ethynyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0418](2S,3R)-6-chloro-3,4-dihydro-7-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0419](2S,3R)-6-chloro-3,4-dihydro-7-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0420](2S,3R)-6-chloro-7-(4-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0421](2S,3R)-6-chloro-7-(4-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0422](2S,3R)-6-chloro-7-(4-cyanophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0423](2S,3R)-6-chloro-7-[4-(trifluoromethyl)phenoxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0424](2S,3R)-6-chloro-7-[4-(trifluoromethoxy)phenoxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0425](2S,3R)-6-chloro-7-(2-bromo-4-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0426] (2S,3R)-6-chloro-7-[(6-bromo-2-naphthyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0427](2S,3R)-6-chloro-7-(2,6-dimethylphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0428](2S,3R)-6-chloro-7-[(4-methoxyphenyl)thio]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0429](2S,3R)-6-chloro-7-[(4-chlorophenyl)thio]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0430](2S,3R)-6-chloro-7-[(4-chlorophenyl)sulfinyl]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0431](2S,3R)-6-chloro-7-[(4-chlorophenyl)sulfonyl]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0432](2S,3R)-6-chloro-7-phenylthio-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0433](2S,3R)-6-chloro-7-(3-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0434](2S,3R)-6-chloro-7-(2,4-dichlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0435](2S,3R)-6-chloro-7-(3,4-difluorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0436](2S,3R)-6-chloro-7-[(6-chloro-2-pyridinyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0437](2S,3R)-6-chloro-7-[(2-chloro-3-pyridinyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0438](2S,3R)-6-chloro-7-[(3-pyridinyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0439](2S,3R)-6-chloro-7-[(2-pyridinyl)oxy]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0440](2S,3R)-6-chloro-7-(4-nitrophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0441](2S,3R)-6-chloro-7-(2-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0442](2S,3R)-6-chloro-7-(4-chloro-3-fluorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0443](2S,3R)-6-chloro-7-(4-carboxyphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0444](2S,3R)-6-chloro-7-(2-chloro-4-carboxyphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0445](2S,3R)-6-chloro-7-(3-carboxyphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0446](2S,3R)-6-chloro-7-(2,2,2-trifluoroethoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0447](2S,3R)-6-chloro-1,2,3,4-tetrahydro-8-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0448](2S,3R)-1,2,3,4-tetrahydro-5-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0449](2S,3R)-1,2,3,4-tetrahydro-6-(4-fluorophenyl)-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0450](2S,3R)-1,2,3,4-tetrahydro-6-ethynyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0451] (2S,3R)-8-bromo-1,2,3,4-tetrahydro-6-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0452](2S,3R)-1,2,3,4-tetrahydro-6-phenylethynyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0453](2S,3R)-6-chloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0454] (2S,3R)-7-ethyl-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0455] (2S,3R)-7-methyl-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0456] (2S,3R)-2,7-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0457](2S,3R)-7-bromo-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0458](2S,3R)-6-chloro-7-methyl-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0459](2S,3R)-8-(1-methylethyl)-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0460](2S,3R)-6-chloro-3,4-dihydro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0461] (2S,3R)-6-chloro-8-(1-methylethyl)-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0462](2S,3R)-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0463](2S,3R)-8-ethoxy-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0464](2S,3R)-7-(1,1-dimethylethyl)-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0465](2S,3R)-6-bromo-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0466](2S,3R)-8-chloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0467](2S,3R)-8-bromo-6-chloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0468]rel-(2R,3S)-3,4-dihydro-6-trifluoromethoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0469](2S,3R)-8-fluoro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0470](2S,3R)-5,7-dichloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0471](2S,3R)-7,8-dichloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0472](2S,3R)-7-isopropyloxy-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0473](2S,3R)-8-phenyl-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0474](2S,3R)-7,8-dimethyl-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0475](2S,3R)-6,8-bis(1,1-dimethylethyl)-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0476](2S,3R)-7-chloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0477](2S,3R)-7-(1-methylethyl)-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0478](2S,3R)-7-phenyl-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0479](2S,3R)-6-chloro-7-ethyl-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0480](2S,3R)-8-ethyl-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0481](2S,3R)-6-chloro-8-ethyl-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0482](2S,3R)-6-chloro-7-phenyl-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0483](2S,3R)-6,7-dichloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0484](2S,3R)-6,8-dichloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0485](2S,3R)-6,8-dibromo-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0486](2S,3R)-6,8-dimethoxy-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0487](2S,3R)-6-nitro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0488](2S,3R)-6-amino-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0489] (2S,3R)-ethyl6-amino-3,4-dihydro-trifluoromethyl-2H-1-benzopyran-3-carboxylate;

[0490](2S,3R)-6-chloro-3,4-dihydro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0491](2S,3R)-8-chloro-3,4-dihydro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0492](2S,3R)-8-chloro-3,4-dihydro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0493](2S,3R)-6,8-difluoro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0494](2S,3R)-6-bromo-8-chloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0495](2S,3R)-8-bromo-3,4-dihydro-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0496](2S,3R)-8-bromo-3,4-dihydro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0497](2S,3R)-8-bromo-3,4-dihydro-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0498](2S,3R)-6-chloro-3,4-dihydro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0499](2S,3R)-6-bromo-3,4-dihydro-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0500](2S,3R)-7-(N,N-diethylamino)-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0501](2S,3R)-3,4-dihydro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0502](2S,3R)-3,4-dihydro-6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0503](2S,3R)-6-aminosulfonyl-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0504](2S,3R)-3,4-dihydro-6-(methylamino)sulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0505](2S,3R)-3,4-dihydro-6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0506](2S,3R)-3,4-dihydro-6-[(1,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0507](2S,3R)-3,4-dihydro-6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0508](2S,3R)-3,4-dihydro-6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0509](2S,3R)-8-chloro-3,4-dihydro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0510] (2S,3R)-6-N,N-diethylaminosulfonyl-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0511](2S,3R)-3,4-dihydro-6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0512](2S,3R)-3,4-dihydro-6-(2,2-dimethylpropylcarbonyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0513](2S,3R)-6,8-dichloro-3,4-dihydro-7-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0514](2S,3R)-6-chloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylicacid;

[0515] (2S, 3R)-6-[[(2-furanylmethyl) amino]sulfonyl]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0516](2S,3R)-6-[(phenylmethyl)sulfonyl]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0517](2S,3R)-6-[[(phenylethyl)amino]sulfonyl]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0518](2S,3R)-3,4-dihydro-6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0519](2S,3R)-6-chloro-8-iodo-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0520](2S,3R)-8-bromo-6-chloro-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0521](2S,3R)-6-formyl-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0522](2S,3R)-6-chloro-8-formyl-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0523](2S,3R)-6-bromo-7-(1,1-dimethylethyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0524]rel-(2R,3S)-5,6-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0525]rel-(2R,3S)-6-cyano-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0526](2S,3R)-6-hydroxymethyl-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0527](2S,3R)-6-(difluoromethyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0528](2S,3R)-2,6-bis(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-3-carboxylicacid;

[0529] rel-(2R,3S)-3,4-dihydro-5,6,7-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0530]rel-(2R,3S)-3,4-dihydro-6,7,8-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0531](2S,3R)-6-(methylthio)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0532](2S,3R)-6-(methylsulfinyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0533]rel-(2R,3S)-5,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0534] (2S,3R)-6-(pentafluoroethyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0535] (2S,3R)-6-(1,1-dimethylethyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0536](2S,3R)-3,4-dihydro-2-(trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzothiopyran-3-carboxylicacid;

[0537] (2S,3R)-6,8-dichloro-7-methyl-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0538](2S,3R)-6-chloro-2,7-bis(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-3-carboxylicacid;

[0539](2S,3R)-5-methoxy-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0540](2S,3R)-6-benzoyl-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0541](2S,3R)-6-(4-chlorobenzoyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0542](2S,3R)-6-(4-hydroxybenzoyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0543](2S,3R)-6-phenoxy-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0544](2S,3R)-8-chloro-6-(4-chlorophenoxy)-3,4-dihydro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0545] (2S,3R)-3,4-dihydro-2-(trifluoroinethyl)-6-[4-(trifluoromethyl)phenoxy)-2H-1-benzopyran-3-carboxylic acid;

[0546](2S,3R)-6-(4-methoxyphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0547](2S,3R)-6-(3-chloro-4-methoxyphenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0548](2S,3R)-6-(4-chlorophenoxy)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0549] (2S,3R)-8-chloro-3,4-dihydro-2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy]-2H-1-benzopyran-3-carboxylicacid;

[0550] (2S,3R)-6-chloro-8-cyano-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0551] (2S, 3R)-6-chloro-8-[(hydroxyimino)methyl]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0552] (2S,3R)-6-chloro-8-(hydroxymethyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0553] (2S,3R)-8-(1H-benzimidazol-2-yl)-6-chloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0554](2S,3R)-3,4-dihydro-7-(1,1-dimethylethyl)-2-(pentafluoroethyl)-2H-1-benzopyran-3-carboxylicacid;

[0555](2S,3R)-6-chloro-8-(methoxymethyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0556](2S,3R)-6-chloro-8-(benzyloxymethyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0557] (2S,3R)-6-chloro-8-ethenyl-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0558] (2S,3R)-6-chloro-8-ethynyl-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0559] (2S,3R)-6-chloro-8-(2-thienyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0560](2S,3R)-6-chloro-8-(2-furanyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0561] (2S,3R)-6-chloro-8-(5-chloro-1-pentynyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0562] (2S,3R)-6-chloro-8-(1-pentynyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0563] (2S,3R)-6-chloro-8-(phenylethynyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0564] (2S,3R)-6-chloro-8-(3,3-dimethyl-1-butynyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0565](2S,3R)-6-chloro-8-[(4-chlorophenyl)ethynyl]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0566] (2S, 3R)-6-chloro-8-[(4-methoxyphenyl)ethynyl]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0567](2S,3R)-6-(phenylethynyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0568] (2S,3R)-6-chloro-8-(4-chlorophenyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0569](2S,3R)-6-chloro-8-(3-methoxyphenyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0570](2S,3R)-6-chloro-8-[(4-methylthio)phenyl]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0571](2S,3R)-6-chloro-8-[(4-methylsulfonyl)phenyl]-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0572](2S,3R)-6-chloro-8-phenyl-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0573](2S,3R)-6-bromo-8-fluoro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0574](2S,3R)-6-(4-fluorophenyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0575](2S,3R)-6-phenyl-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0576](2S,3R)-8-chloro-6-fluoro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0577](2S,3R)-6,8-diiodo-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0578] (2S,3R)-6-(5-chloro-2-thienyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0579](2S,3R)-6-(2-thienyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0580](2S,3R)-6-(4-chlorophenyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0581](2S,3R)-6-(4-bromophenyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0582] (2S,3R)-6-(ethynyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0583] (2S,3R)-6-methyl-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0584] (2S,3R)-6-chloro-3,4-dihydro-8-(4-methoxyphenyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0585](2S,3R)-6-chloro-3,4-dihydro-2-(trifluoromethyl)-4-ethenyl-2H-1-benzopyran-3-carboxylicacid;

[0586](2S,3R)-6-chloro-3,4-dihydro-2-(trifluoromethyl)-4-phenyl-2H-1-benzopyran-3-carboxylicacid;

[0587](2S,3R)-6-chloro-4-(2-thienyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0588](2S,3R)-6-(2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0589](2S,3R)-3,4-dihydro-6-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0590](2S,3R)-3,4-dihydro-6,8-dimethyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0591](2S,3R)-3,4-dihydro-6-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0592](2S,3R)-3,4-dihydro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0593](2S,3R)-3,4-dihydro-6,7-dimethyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0594](2S,3R)-3,4-dihydro-8-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0595](2S,3R)-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0596](2S,3R)-6-chloro-3,4-dihydro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0597](2S,3R)-7-chloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0598](2S,3R)-6,7-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0599] (2S,3R)-3,4-dihydro-2-(trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzopyran-3-carboxylic acid;

[0600]rel-(2R,3S)-6,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0601](2S,3R)-6-chloro-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0602](2S,3R)-6,8-dichloro-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0603] (2S,3R)-6,7-difluoro-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0604](2S,3R)-6-iodo-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0605] (2S,3R)-6-bromo-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0606](2S,3R)-1,2,3,4-tetrahydro-6-(trifluoromethoxy)-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0607](2S,3R)-6-(trifluoromethyl)-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0608] (2S,3R)-6-cyano-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0609] (2S,3R)-6-chloro-1,2,3,4-tetrahydro-1-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0610](2S,3R)-6-chloro-1,2,3,4-tetrahydro-2-(trifluoromethyl)-1-[[4-(trifluoromethyl)phenyl]methyl]-3-quinolinecarboxylicacid;

[0611](2S,3R)-6-chloro-1-[(4-chlorophenyl)methyl]-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0612](2S,3R)-6-chloro-1,2,3,4-tetrahydro-2-(trifluoromethyl)-1-[[4-(methoxy)phenyl]methyl]-3-quinolinecarboxylicacid;

[0613](2S,3R)-6-chloro-1-[(4-cyanophenyl)methyl]-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0614](2S,3R)-6-chloro-1,2,3,4-tetrahydro-1-[(4-nitrophenyl)methyl]-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0615] (2S,3R)-6-chloro-1,2,3,4-tetrahydro-1-ethyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0616] (2S, 3R)-6-chloro-2-(triflouromethyl)-1,2,3,4-tetrahydro [1,8]napthyridine-3-carboxylic acid;

[0617] (2S, 3R)-3,4-dihydro-2-trifluoromethyl-2H-naphtho [1,2-b]pyran-3-carboxylic acid;

[0618] (2S, 3R)-3,4-dihydro-2-trifluoromethyl-3H-naptho[2,1-b]pyran-3-carboxylic acid;

[0619] (2S,3R)-3,4-dihydro-2-trifluoromethyl-2H-naphtho[2,3-b]pyran-3-carboxylicacid; and

[0620] (2S,3R)-3,4-dihydro-5-(hydroxymethyl)-8-methyl-2-(trifluoromethyl)-2H-pyrano[2,3-c] pyridine-3-carboxylic acid.

[0621] The term “hydrido” denotes a single hydrogen atom (H). Thishydrido radical may be attached, for example, to an oxygen atom to forma hydroxyl radical or two hydrido radicals may be attached to a carbonatom to form a methylene (—CH₂—) radical. Where the term “alky1” isused, either alone or within other terms such as “haloalkyl” and“alkylsulfonyl”, it embraces linear or branched radicals having one toabout twelve carbon atoms or, preferably, one to about eight carbonatoms. More preferred alkyl radicals are “lower alkyl” radicals havingone to about six carbon atoms. Examples of such radicals include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,pentyl, iso-amyl, hexyl and the like. Even more preferred are loweralkyl radicals having one to four carbon atoms. The term “alkenyl”embraces linear or branched radicals having at least one carbon-carbondouble bond of two to about twelve carbon atoms or, preferably, two toabout eight carbon atoms. More preferred alkenyl radicals are “loweralkenyl” radicals having two to about six carbon atoms. Examples ofalkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and4-methylbutenyl.

[0622] The term “alkynyl” denotes linear or branched radicals having twoto about twelve carbon atoms or, preferably, two to about eight carbonatoms. More preferred alkynyl radicals are “lower alkynyl” radicalshaving two to about six carbon atoms. Most preferred are lower alkynylradicals having two to about four carbon atoms. Examples of suchradicals include propargyl, butynyl, and the like. The alkenyl andalkynyl radicals may be substituted with halo atoms to form“haloalkynyl” and “haloalkenyl” radicals. The terms “alkenyl” and “loweralkenyl”, embrace radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations. The term “halo” means halogenssuch as fluorine, chlorine, bromine or iodine atoms. The term“haloalkyl” embraces radicals wherein any one or more of the alkylcarbon atoms is substituted with halo as defined above. Specificallyembraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. Amonohaloalkyl radical, for one example, may have either an iodo, bromo,chloro or fluoro atom within the radical. Dihalo and polyhaloalkylradicals may have two or more of the same halo atoms or a combination ofdifferent halo radicals. “Lower haloalkyl” embraces radicals having 1-6carbon atoms. Examples of haloalkyl radicals include fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Perfluoroalkyl” meansalkyl radicals having all hydrogen atoms replaced with fluoro atoms.Examples include trifluoromethyl and pentafluoroethyl. The term“hydroxyalkyl” embraces linear or branched alkyl radicals having one toabout ten carbon atoms any one of which may be substituted with one ormore hydroxyl radicals. More preferred hydroxyalkyl radicals are “lowerhydroxyalkyl” radicals having one to six carbon atoms and one or morehydroxyl radicals. Examples of such radicals include hydroxymethyl,hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even morepreferred are lower hydroxyalkyl radicals having one to three carbonatoms. The term “cyanoalkyl” embraces linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which may be substitutedwith one cyano radicals. More preferred cyanoalkyl radicals are “lowercyanoalkyl” radicals having one to six carbon atoms and one cyanoradical. Even more preferred are lower cyanoalkyl radicals having one tothree carbon atoms. Examples of such radicals include cyanomethyl. Theterm “alkoxy” embraces linear or branched oxy-containing radicals eachhaving alkyl portions of one to about ten carbon atoms. More preferredalkoxy radicals are “lower alkoxy” radicals having one to six carbonatoms. Examples of such radicals include methoxy, ethoxy, propoxy,butoxy and tert-butoxy. Even more preferred are lower alkoxy radicalshaving one to three carbon atoms. The “al koxy” radicals may be furthersubstituted with one or more halo atoms, such as fluoro, chloro orbromo, to provide “haloalkoxy” radicals. Even more preferred are lowerhaloalkoxy radicals having one to three carbon atoms. Examples of suchradicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term “aryl”, aloneor in combination, means a carbocyclic aromatic system containing one ortwo rings wherein such rings may be attached together in a pendentmanner or may be fused. The term “aryl” embraces aromatic radicals suchas phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Morepreferred aryl is phenyl. Said “aryl” group may have 1 to 3 substituentssuch as lower alkyl, hydroxy, halo, lower haloalkyl, nitro, cyano, loweralkoxy and lower alkylamino. The term “heterocyclyl” embraces 5-10membered saturated, partially saturated and unsaturatedheteroatom-containing ring-shaped radicals, where the heteroatoms may beselected from nitrogen, sulfur and oxygen. Examples of saturatedheterocyclic radicals include saturated 3 to 6-membered heteromonocylicgroup containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl,imidazolidinyl, piperidino, piperazinyl]; saturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturatedheterocyclyl radicals include dihydrothiophene, dihydropyran,dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclicradicals, also termed “heteroaryl” radicals, include unsaturated 5 to 6membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl[e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl];unsaturated condensed heterocyclic group containing 1 to 5 nitrogenatoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl[e.g., tetrazolo [1,5-b]pyridazinyl]; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, f or example, pyranyl,2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclicgroup containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated condensed heterocyclic group containing1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl,benzoxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl]; unsaturated condensed heterocyclic group containing1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl,benzothiadiazolyl] and the like. The term also embraces 9-10 memberedradicals where heterocyclic radicals are fused with aryl radicals.Examples of such fused bicyclic radicals include benzofuran, quinolyl,benzothiophene, and the like. Said “heterocyclyl” group may have 1 to 3substituents such as lower alkyl, hydroxy, oxo, amino and loweralkylamino. Preferred heterocyclic radicals include five to ten memberedf used or unfused radicals. More preferred examples of heteroarylradicals include benzofuryl, 2,3-dihydrobenzofuryl, benzothienyl,indolyl, dihydroindolyl, chromanyl, benzopyran, thiochromanyl,benzothiopyran, benzodioxolyl, benzodioxanyl, pyridyl, thienyl,thiazolyl, oxazolyl, furyl, and pyrazinyl. Even more preferredheteroaryl radicals are 5- or 6-membered heteroaryl, containing one ortwo heteroatoms selected from sulfur nitrogen and oxygen, selected fromthienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl. The term“sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals —SO₂—.“Alkylsulfonyl” embraces alkyl radicals attached to a sulfonyl radical,where alkyl is defined as above. More preferred alkylsulfonyl radicalsare “lower alkylsulfonyl” radicals having one to six carbon atoms. Evenmore preferred are lower alkylsulfonyl radicals having one to threecarbon atoms. Examples of such lower alkylsulfonyl radicals includemethylsulfonyl, ethylsulfonyl and propylsulfonyl. “Haloalkylsulfonyl”embraces haloalkyl radicals attached to a sulfonyl radical, wherehaloalkyl is defined as above. More preferred haloalkylsulfonyl radicalsare “lower haloalkylsulfonyl” radicals having one to six carbon atoms.Even more preferred are lower haloalkylsulfonyl radicals having one tothree carbon atoms. Examples of such lower haloalkylsulfonyl radicalsinclude trifluoromethylsulfonyl. The term “arylalkylsulfonyl” embracesaryl radicals as defined above, attached to an alkylsulfonyl radical.Examples of such radicals include benzylsulfonyl andphenylethylsulfonyl. The term “heterocyclylsulfonyl” embracesheterocyclyl radicals as defined above, attached to a sulfonyl radical.More preferred heterocyclylsulfonyl radicals contain 5-7 memberedheterocyclyl radicals containing one or two heteroatoms. Examples ofsuch radicals include tetrahydropyrrolylsulfonyl morpholinylsulfonyl andazepinylsulfonyl. The terms “sulfamyl,” “aminosulfonyl” and“sulfonamidyl, ” whether alone or used with terms such as“N-alkylaminosulfonyl”, “N-arylaminosulfonyl”,“N,N-dialkylaminosulfonyl” and “N-alkyl-N-arylaminosulfonyl”, denotes asulfonyl radical substituted with an amine radical, forming asulfonamide (—SO₂NH₂). The term “alkylaminosulfonyl” includes“N-alkylaminosulfonyl” and “N,N-dialkylaminosulfonyl” where sulfamylradicals are substituted, respectively, with one alkyl radical, or twoalkyl radicals. More preferred alkylaminosulfonyl radicals are “loweralkylaminosulfonyl” radicals having one to six carbon atoms. Even morepreferred are lower alkylaminosulfonyl radicals having one to threecarbon atoms. Examples of such lower alkylaminosulfonyl radicals includeN-methylaminosulfonyl, N-ethylaminosulfonyl andN-methyl-N-ethylaminosulfonyl. The terms “N-arylaminosulfonyl” and“N-alkyl-N-arylaminosulfonyl” denote sulfamyl radicals substituted,respectively, with one aryl radical, or one alkyl and one aryl radical.More preferred N-alkyl-N-arylaminosulfonyl radicals are “lowerN-alkyl-N-arylsulfonyl” radicals having alkyl radicals of one to sixcarbon atoms. Even more preferred are lower N-alkyl-N-arylaminosulfonylradicals having one to three carbon atoms. Examples of such lowerN-alkyl-N-aryl-aminosulfonyl radicals includeN-methyl-N-phenylaminosulfonyl and N-ethyl-N-phenylaminosulfonyl.Examples of such N-aryl-aminosulfonyl radicals includeN-phenylaminosulfonyl. The term “arylalkylaminosulfonyl” embracesaralkyl radicals as described above, attached to an aminosulfonylradical. More preferred are lower arylalkylaminosulfonyl radicals havingone to three carbon atoms. The term “heterocyclylaminosulfonyl” embracesheterocyclyl radicals as described above, attached to an aminosulfonylradical. The term “heteroarylalkylaminosulfonyl” embracesheteroarylalkyl radicals as described above, attached to anaminosulfonyl radical. The terms “N-heteroarylaminosulfonyl” and“N-alkyl-N-heteroarylaminosulfonyl” denote sulfamyl radicalssubstituted, respectively, with one heteroaryl radical, or one alkyl andone heteroaryl radical. More preferred N-alkyl-N-heteroarylaminosulfonylradicals are “lower N-alkyl-N-heteroarylsulfonyl” radicals having alkylradicals of one to six carbon atoms. Even more preferred are lowerN-alkyl-N-heteroarylaminosulfonyl radicals having one to three carbonatoms. The terms “carboxy” or “carboxyl”, whether used alone or withother terms, such as “carboxyalkyl”, denotes —CO₂H. The term“carboxyalkyl” embraces radicals having a carboxy radical as definedabove, attached to an alkyl radical. The term “carbonyl”, whether usedalone or with other terms, such as “alkylcarbonyl”, denotes —(C═O)—. Theterm “alkylcarbonyl” embraces radicals having a carbonyl radicalsubstituted with an alkyl radical. More preferred alkylcarbonyl radicalsare “lower alkylcarbonyl” radicals having one to six carbon atoms. Evenmore preferred are lower alkylcarbonyl radicals having one to threecarbon atoms. Examples of such radicals include methylcarbonyl andethylcarbonyl. The term “haloalkylcarbonyl” embraces radicals having acarbonyl radical substituted with an haloalkyl radical. More preferredhaloalkylcarbonyl radicals are “lower haloalkylcarbonyl” radicals havingone to six carbon atoms. Even more preferred are lower haloalkylcarbonylradicals having one to three carbon atoms. Examples of such radicalsinclude trifluoromethylcarbonyl. The term “arylcarbonyl” embracesradicals having a carbonyl radical substituted with an aryl radical.More preferred arylcarbonyl radicals include phenylcarbonyl. The term“heteroarylcarbonyl” embraces radicals having a carbonyl radicalsubstituted with a heteroaryl radical. Even more preferred are 5- or6-membered heteroarylcarbonyl radicals. The term “arylalkylcarbonyl”embraces radicals having a carbonyl radical substituted with anarylalkyl radical. More preferred radicals arephenyl-C₁-C₃-alkylcarbonyl, including benzylcarbonyl. The term“heteroarylalkylcarbonyl” embraces radicals having a carbonyl radicalsubstituted with a heteroarylalkyl radical. Even more preferred arelower heteroarylalkylcarbonyl radicals having 5-6-membered heteroarylradicals attached to alkyl portions having one to three carbon atoms.The term “alkoxycarbonyl” means a radical containing an alkoxy radical,as defined above, attached via an oxygen atom to a carbonyl radical.Preferably, “lower alkoxycarbonyl” embraces alkoxy radicals having oneto six carbon atoms. Examples of such “lower alkoxycarbonyl” esterradicals include substituted or unsubstituted methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonylEven more preferred are lower alkoxycarbonyl radicals having alkoxyportions of one to three carbon atoms. The term “aminocarbonyl” whenused by itself or with other terms such as “aminocarbonylalkyl”,“N-alkylaminocarbonyl ”, “N-arylaminocarbonyl”,“N,N-dialkylaminocarbonyl”, “N-alkyl-N-arylaminocarbonyl”,“N-alkyl-N-hydroxyaminocarbonyl” and“N-alkyl-N-hydroxyaminocarbonylalkyl”, denotes an amide group of theformula —C(═O)NH₂. The terms “N-alkylaminocarbonyl” and“N,N-dialkylaminocarbonyl” denote aminocarbonyl radicals which have beensubstituted with one alkyl radical and with two alkyl radicals,respectively. More preferred are “lower alkylaminocarbonyl” having loweralkyl radicals as described above attached to an aminocarbonyl radical.The terms “N-arylaminocarbonyl” and “N-alkyl-N-arylaminocarbonyl” denoteaminocarbonyl radicals substituted, respectively, with one aryl radical,or one alkyl and one aryl radical. The term “alkylsulfonylaminocarbonyl”denotes aminocarbonyl radicals substituted with one alkylsulfonylradical. The term “cycloalkyl” embraces saturated carbocyclic radicalshaving three to about eight carbon atoms. More prefferred cycloalkylradicals are “lower cycloalkyl” radicals of four to seven carbon atoms.Examples include cyclobutyl, cyclopentenyl and cyclohexyl. The term“N-cycloalkylaminocarbonyl” denoted aminocarbonyl radicals which havebeen substituted with at least one cycloalkyl radical. More preferredare “lower cycloalkylaminocarbonyl” having lower cycloalkyl radicals ofthree to seven carbon atoms, attached to an aminocarbonyl radical. Theterm “aminoalkyl” embraces alkyl radicals substituted with one or moreamino radicals. The term “alkylaminoalkyl” embraces aminoalkyl radicalshaving the amino nitrogen atom substituted with an alkyl radical. Evenmore preferred are lower alkylaminoalkyl radicals having one to threecarbon atoms. The term “heterocyclylalkyl” embracesheterocyclic-substituted alkyl radicals. More preferredheterocyclylalkyl radicals are “5- or 6-membered heteroarylalkyl”radicals having alkyl portions of one to six carbon atoms and a 5- or6-membered heteroaryl radical. Even more preferred are lowerheteroarylalkyl radicals having alkyl portions of one to three carbonatoms. Examples include such radicals as pyridylmethyl andthienylmethyl. The term “aralkyl” embraces aryl-substituted alkylradicals. Preferable aralkyl radicals are “lower aralkyl” radicalshaving aryl radicals attached to alkyl radicals having one to six carbonatoms. Even more preferred are lower aralkyl radicals phenyl attached toalkyl portions having one to three carbon atoms. Examples of suchradicals include benzyl, diphenylmethyl and phenylethyl. The termsbenzyl and phenylmethyl are interchangeable. The aryl in said aralkylmay be additionally substituted with halo, lower alkyl, lower alkoxy,lower halkoalkyl and lower haloalkoxy. The term “arylalkenyl” embracesaryl-substituted alkenyl radicals Preferable arylalkenyl radicals are“lower arylalkenyl” radicals having aryl radicals attached to alkenylradicals having two to six carbon atoms. Examples of such radicalsinclude phenylethenyl. The aryl in said arylalkenyl may be additionallysubstituted such as with halo, lower alkyl, lower alkoxy, lowerhalkoalkyl and lower haloalkoxy The term “arylalkynyl” embracesaryl-substituted alkynyl radicals. Preferable arylalkynyl radicals are“lower arylalkynyl” radicals having aryl radicals attached to alkynylradicals having two to six carbon atoms. Examples of such radicalsinclude phenylethynyl. The aryl in said aralkyl may be additionallysubstituted such as with halo, lower alkyl, lower alkoxy, lowerhalkoalkyl and lower haloalkoxy. The term “alkylthio” embraces radicalscontaining a linear or branched alkyl radical, of one to ten carbonatoms, attached to a divalent sulfur atom. Even more preferred are loweralkylthio radicals having one to three carbon atoms. An example of“alkylthio” is methylthio, (CH₃—S—). The term “haloalkylthio” embracesradicals containing a haloalkyl radical, of one to ten carbon atoms,attached to a divalent sulfur atom. Even more preferred are lowerhaloalkylthio radicals having one to three carbon atoms. An example of“haloalkylthio” is trifluoromethylthio. The term “alkylsulfinyl”embraces radicals containing a linear or branched alkyl radical, of oneto ten carbon atoms, attached to a divalent —S(═O)— atom. More preferredare lower alkylsulfinyl radicals having one to three carbon atoms. Theterm “arylsulfinyl” embraces radicals containing an aryl radical,attached to a divalent —S(═O)— atom. Even more preferred are optionallysubstituted phenylsulfinyl radicals. The term “haloalkylsulfinyl”embraces radicals containing a haloalkyl radical, of one to ten carbonatoms, attached to a divalent —S(═O)— atom. Even more preferred arelower haloalkylsulfinyl radicals having one to three carbon atoms. Theterms “N-alkylamino” and “N,N-dialkylamino” denote amino groups whichhave been substituted with one or two alkyl radicals. More preferredalkylamino radicals are “lower alkylamino” radicals having one or twoalkyl radicals of one to six carbon atoms, attached to a nitrogen atom.Even more preferred are lower alkylamino radicals having one to threecarbon atoms. Suitable “alkylamino” may be mono or dialkylamino such asN-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or thelike. The term “arylamino” denotes amino groups which have beensubstituted with one or two aryl radicals, such as N-phenylamino. The“arylamino” radicals may be further substituted on the aryl ring portionof the radical. The term “heteroarylamino” denotes amino groups whichhave been substituted with one or two heteroaryl radicals, such asN-thienylamino. The “heteroarylamino” radicals may be furthersubstituted on the heteroaryl ring portion of the radical. The term“aralkylamino” denotes amino groups which have been substituted with oneor two aralkyl radicals. More preferred are phenyl-C₁-C₃-alkylaminoradicals, such as N-benzylamino. The “aralkylamino” radicals may befurther substituted on the aryl ring portion of the radical. The terms“N-alkyl-N-arylamino” and “N-aralkyl-N-alkylamino” denote amino groupswhich have been substituted with one aralkyl and one alkyl radical, orone aryl and one alkyl radical, respectively, to an amino group. Theterm “heteroarylalkylamino” denotes amino groups which have beensubstituted with one or two heteroarylalkyl radicals. The“heteroarylalkylamino” radicals may be further substituted on theheteroaryl ring portion of the radical. The terms“N-alkyl-N-heteroarylamino” and “N-heteroarylalkyl-N-alkylamino” denoteamino groups which have been substituted with one heteroarylalkyl andone alkyl radical, or one heteroaryl and one alkyl radical,respectively, to an amino group. The term “arylthio” embraces arylradicals of six to ten carbon atoms, attached to a divalent sulfur atom.An example of “arylthio” is phenylthio. The term “aralkylthio” embracesaralkyl radicals as described above, attached to a divalent sulfur atom.More preferred are phenyl-C₁-C₃-alkylthio radicals. An example of“aralkylthio” is benzylthio. The term “aralkylsulfonyl” embraces aralkylradicals as described above, attached to a divalent sulfonyl radical.More preferred are phenyl-C₁-C₃-alkylsulfonyl radicals. The term“aryloxy” embraces optionally substituted aryl radicals, as definedabove, attached to an oxygen atom. Examples of such radicals includephenoxy. The term “heteroaryloxy” embraces optionally substitutedheteroaryl radicals, as defined above, attached to an oxygen atom. Theterm “aralkoxy” embraces oxy-containing aralkyl radicals attachedthrough an oxygen atom to other radicals. More preferred aralkoxyradicals are “lower aralkoxy” radicals having optionally substitutedphenyl radicals attached to lower alkoxy radical as described above.Examples of such radicals include benzyloxy. The term “alkoxyalkyl”embraces alkoxy radicals attached through an oxygen atom to alkylradicals. More preferred alkoxyalkyl radicals are “lower alkoxyalkyl”radicals having lower alkoxy radicals attached to lower alkoxy radicalas described above. The term “arylalkoxyalkyl” embraces arylalkoxyradicals attached through an oxygen atom to alkyl radicals. Morepreferred arylalkoxyalkyl radicals are “lower arylalkoxyalkyl” radicalshaving optionally substituted aryl radicals attached to loweralkoxyalkyl radical as described above. The term “heteroarylalkoxy”embraces oxy-containing heteroarylalkyl radicals attached through anoxygen atom to alkyl radicals. More preferred heteroarylalkoxy radicalsare “lower heteroarylalkoxy” radicals having optionally substitutedheteroaryl radicals attached to lower alkoxy radical as described above.

[0623] The present invention comprises a pharmaceutical compositioncomprising a therapeutically-effective amount of a compound of FormulaI-IV in association with at least one pharmaceutically-acceptablecarrier, adjuvant or diluent.

[0624] The present invention also comprises a method of treatingcyclooxygenase-2 mediated disorders, such as inflammation, in a subject,the method comprising treating the subject having or susceptible to suchdisorder with a therapeutically-effective amount of a compound ofFormula I-IV.

[0625] Also included in the family of compounds of Formula I-IV are thestereoisomers thereof. Compounds of the present invention can possessone or more asymmetric carbon atoms and are thus capable of existing inthe form of optical isomers as well as in the form of racemic ornon-racemic mixtures thereof. Accordingly, some of the compounds of thisinvention may be present in racemic mixtures which are also included inthis invention. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, for example byformation of diastereoisomeric salts by treatment with an opticallyactive base and then separation of the mixture of diastereoisomers bycrystallization, followed by liberation of the optically active basesfrom these salts. Examples of appropriate bases are brucine, strychnine,dehydroabietylamine, quinine, cinchonidine, ephedrine,a-methylbenzylamine, amphetamine, deoxyphedrine, chloramphenicolintermediate, 2-amino-1-butanol, and 1-(1-napthyl)ethylamine. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules. The synthesizeddiastereoisomers can be separated by conventional means such aschromatography, distillation, crystallization or sublimation, and thenhydrolyzed to deliver the enantiomerically pure compound. The opticallyactive compounds of Formula I can likewise be obtained by utilizingoptically active starting materials. These isomers may be in the form ofa free acid, a free base, an ester or a salt. Additional methods forresolving optical isomers, known to those skilled in the art may beused, for example, those discussed by J. Jaques et al in Enantiomers,Racemates, and Resolutions, John Wiley and Sons, New York (1981).

[0626] Also included in the family of compounds of Formula I-IV are theprotected acids thereof, such as the esters, hydroxyamino derivatives,amides and sulfonamides, to form the active compounds in vivo. Thusprimary and secondary amines can be reacted with thedihydrochromene-3-carboxylic acids of Formula I-IV to form amides whichcan be useful as prodrugs to form the active compounds in vivo.Preferred amines heterocyclicamines, including optionally substitutedaminothiazoles, optionally substituted amino-isoxazoles, and optionallysubstituted aminopyridines; aniline derivatives; sulfonamides;aminocarboxylic acids; and the like. Additionally,1-acyldihydroquinolines can behave as prodrugs for the1H-dihydroquinolines. The esters, hydroxyamino derivatives andsulfonamides can be prepared from the acids by methods known to oneskilled in the art.

[0627] Also included in the family of compounds of Formula I-IV are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I-IV may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, algenic, β-hydroxybutyric, galactaricand galacturonic acid. Suitable pharmaceutically-acceptable baseaddition salts of compounds of Formula I-IV include metallic salts, suchas salts made from aluminum, calcium, lithium, magnesium, potassium,sodium and zinc, or salts made from organic bases including primary,secondary and tertiary amines, substituted amines including cyclicamines, such as caffeine, arginine, choline, diethylamine,2-dimethylaminoethanol, 2-diethylaminoethanol, ethanolamine,N-ethylpiperidine, histidine, glucamine, glucosamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,procaine, purines, theobromine, triethylamine, trimethylamine, andtripropylamine. All of these salts may be prepared by conventional meansfrom the corresponding compound of the invention by reacting, forexample, the appropriate acid or base with the compound of Formula I-IV.

General Synthetic Procedures

[0628] The compounds of the invention can be synthesized according tothe following procedures of Schemes 1-17, wherein the R¹—R⁶ substituentsare as defined for Formulas I-IV, above, except where further noted.

[0629] Synthetic Scheme 1 illustrates the general method for thepreparation of a wide variety of substituted 2H-1-benzopyran derivatives3 and 4. In step 1, a representative ortho-hydroxybenzaldehyde(salicylaldehyde) derivative 1 is condensed with an acrylate derivative2 in the presence of base, such as potassium carbonate in a solvent suchas dimethylformamide, to afford the desired 2H-1-benzopyran ester 3. Analternative base-solvent combination for this condensation includes anorganic base such as triethylamine and a solvent such as dimethylsulfoxide. In step 2 the-ester is hydrolyzed to the corresponding acid,such as by treatment with aqueous base (sodium hydroxide) in a suitablesolvent such as ethanol to afford after acidification the substituted2H-1-benzopyran-3-carboxylic acid 4.

[0630] Synthetic Scheme 2 shows the general method for functionalizingselected 2H-1-benzopyrans. Treatment of the 2H-1-benzopyran carboxylicacid 4 or ester 3 with an electrophilic agent makes a 6-substituted2H-1-benzopyran 5. A wide variety of electrophillic agents reactselectively with 2H-1-benzopyrans 4 in the 6-position to provide newanalogs in high yield. Electrophilic reagents such as halogen (chlorineor bromine) give the 6-halo derivatives. Chlorosulfonic acid reacts toafford the 6-position sulfonyl chloride that can further be converted toa sulfonamide or sulfone. Friedel-Crafts acylation of 4 provides6-acylated 2H-1-benzopyrans in good to excellent yield. A number ofother electrophiles can be used to selectively react with these2H-1-benzopyrans in a similar manner. A 6-position substituted2H-1-benzopyran can react with an electrophilic reagent at the8-position using similar chemistries to that described for electrophilicsubstitution of the 6-position. This yields an 2H-1-benzopyran which issubstituted at both the 6 and 8 positions.

[0631] Synthetic Scheme 3 illustrates a second general synthesis ofsubstituted 2H-1-benzopyran-3-carboxylic acids which allows substitutionat position 4 of the 2H-1-benzopyran. In this case a commercially orsynthetically available subtituted ortho-hydroxy acetophenone 6 istreated with two or more equivalents of a strong base such as lithiumbis(trimethylsilyl)amide in a solvent such as tetrahydrofuran (THF),followed by reaction with diethyl carbonate to afford the beta-ketoester 7. Ester 7 is condensed with an acid chloride or anhydride in thepresence of a base such as potassium carbonate in a solvent such astoluene with heat to afford 4-oxo-4H-1-benzopyran 8. Reduction of theolefin can be accomplished by a variety of agents including sodiumborohydride (NaBiH₄) in solvent mixtures such as ethanol andtetrahydrofuran (THF), or by use of triethylsilane in a solvent such astrifluoroacetic acid, or by catalytic reduction using palladium oncharcoal and hydrogen gas in a solvent such as ethanol to yield the newbeta-keto ester 9 (two tautomeric structures shown). Acylation of theoxygen of the ketone enolate in the presence of a base such as2,6-di-tert-butyl-4-methylpyridine, an acylating agent such astrifluoromethanesulfonic anhydride, and using a solvent such asmethylene chloride yields the enol-triflate 10. Triflate 10 can bereduced with reagents such as tri-n-butyltin hydride, lithium chlorideand a palladium (O) catalyst such astetrakis(triphenylphosphine)palladium (0) in a solvent such astetrahydrofuran to yield 2H-1-benzopyran ester 11 where R″ is hydrogen.The ester 11 can be saponified with a base such as 2.5 N sodiumhydroxide in a mixed solvent such as tetrahydrofuran-ethanol-water(7:2:1) to yield the desired substituted 2H-1-benzopyran-3-carboxylicacid.

[0632] To incorporate a carbon fragment R″ one can treat triflate 10with reagents known to undergo “cross-coupling” chemistries such atributylethenyltin, lithium chloride and a palladium (0) catalyst suchas tetrakis(triphenylphosphine)palladium (0) in a solvent such astetrahydrofuran to yield 2H-1-benzopyran ester 11 where R¹ is a vinylmoiety. The ester 6 can be saponified with a base such as 2.5 N sodiumhydroxide in a mixed solvent such as tetrahydrofuran-ethanol-water(7:2:1) to yield the desired 4-vinyl-2H-1-benzopyran-3-carboxylic acid(12, R″═CHCH₂). Similarly triflate 10 can be converted under similarconditions using tri-n-butylphenyltin to 2H-1-benzopyran where R³=phenyland by hydrolysis of the ester converted to the carboxylic acid 12 whereR″=phenyl. Using a similar strategy, substituents which be incorporatedas substitutent R″ can be substituted olefins, substituted aromatics,substuted heteroaryl, acetylenes and substituted acetylenes.

[0633] Synthetic Scheme 4 shows an alternative general procedure for thepreparation of 4-oxo-4H-1-benzopyran 8. Treatment of anortho-fluorobenzoyl chloride with an appropriately substituted beta-ketoester 14 with a base such as potassium carbonate in a solvent such astoluene provides 4-oxo-4H-1-benzopyran 8. 4-Oxo-4H-1-benzopyran 8 can beconverted to 2H-1-benzopyran 12 as described in Scheme 3.

[0634] Synthetic Scheme 5 shows a general method for substitution of thearomatic ring of the 2H-1-benzopyran. This can be accomplished throughorgano-palladium mediated “cross-coupling” chemistries using a palladium(0) catalyst to couple benzopyran 15 at position Y, where Y is iodide,bromide or triflate, with an acetylene, olefin, nitrile, or arylcoupling agent. Substituted acetylenes as the coupling agent willprovide the corresponding substituted acetylene. Substituted arylmoieties can be incorporated using arylboronic acids or esters; nitrilesriles can be incorporated by use of zinc (II) cyanide. The resultingester 16 can be converted to carboxylic acid 17 as described in Scheme1.

[0635] Another approach to substitution of the aryl moiety of thebenzopyran 15 is to convert Y, where Y is iodide or bromide, to aperfluoroalkyl moiety. Exemplary of this transformation is theconversion of 15 (Y=iodide) to 16 (R^(2′)=pentafluoroethyl) using apotassium pentafluoropropionate and copper (I) iodide inhexamethylphosphoramide (HMPA). The resulting ester 16 can be convertedto carboxylic acid 15 as described in Scheme 1.

[0636] A similar method adds substitution of the aromatic ring indihydroquinoline-3-carboxylates. This can be accomplished throughorganopalladium couplings with aryl iodides, bromides, or triflates andvarious coupling agents (R. F. Heck, Palladium Reagents in OrganicSynthesis. Academic Press 1985). When using a suitable palladiumcatalystsuch as tetrakis(triphenyl-phospine)palladium(0) in this reaction,coupling agents such as alkynes provide disubstituted alkynes, phenylboronic acids afford biphenyl compounds, and cyanides produce arylcyanocompounds. A number of other palladium catalysts and coupling reagentscould be used to selectively react with appropriately substituteddihydroquinoline-3-carboxylates in a similar maner.

[0637] Synthetic Scheme 6 shows a general synthetic route for conversionof a commercially or synthetically available substituted phenol into asubstituted salicylaldehyde. Several different methods which utilizeformaldehyde or a chemically equivalent reagent are described in detailbelow.

[0638] Reaction of an appropriately substitutedphenol 18 in basic mediawith formaldehyde (or chemical equivalent) will yield the correspondingsalicylaldehyde 1. The intermediate, ortho-hydroxymethylphenol 19, willunder appropriate reaction conditions be oxidized to the salicylaldehyde1 in situ. The reaction commonly employs ethyl magnesium bromide ormagnesium methoxide (one equivalent) as the base, toluene as thesolvent, paraformaldehyde (two or more equivalents) as the source offormaldehyde, and employs hexamethylphoramide (HMPA) orN,N,N′,N′-tetramethylethylenediamine (TMEDA). (See: Casiraghi, G. etal., J. C. S. Perkin 1,1978, 318-321.)

[0639] Alternatively an appropriately substituted phenol 18 may reactwith formaldehyde under aqueous basic conditions to form the substitutedortho-hydroxybenzyl alcohol 19 (See: a) J. Leroy and C. Wakselman, J.Fluorine Chem., 40, 23-32 (1988). b) A. A. Moshfegh, et al., Helv. Chi.Acta., 65, 1229-1232 (1982)). Commonly used bases include aqueouspotassium hydroxide or sodium hydroxide. Formalin (38% formaldehyde inwater) is commonly employed as the source of formaldehyde. The resultingortho-hydroxybenzyl alcohol 19 can be converted to the salicylaldehyde 1by an oxidizing agent such as manganese (IV) dioxide in a solvent suchas methylene chloride or chloroform (See: R-G. Xie, et al., SyntheticCommun. 24, 53-58 (1994)).

[0640] An appropriately substituted phenol 18 can be treated underacidic conditions with hexamethylenetetramine (HMTA) to prepare thesalicylaldehyde 1 (Duff Reaction; See: Y. Suzuki, and H. Takahashi,Chem. Pharm. Bull., 31, 1751-1753 (1983)). This reaction commonlyemploys acids such as acetic acid, boric acid, methanesulfonic acid, ortrifluoromethanesulfonic acid. The source of formaldehyde commonly usedis hexamethylenetetramine.

[0641] Synthetic Scheme 7 shows the Reimer-Tiemann reaction in which acommercially or synthetically available appropriately substituted phenol18 will under basic conditions react with chloroform to yield asubstituted salicylaldehyde 1 (See: Cragoe, E. J.; Schultz, E. M., U.S.Pat. No. 3,794,734, 1974).

[0642] Synthetic Scheme 8 shows the conversion of a commercially orsynthetically available appropriately substituted salicylic acid 21 toits respective salicylaldehyde 1 via an intermediate 2-hydroxybenzylalcohol 19. Reduction of the salicylic acid 21 can be accomplished witha hydride reducing agent such as borane in a solvent such astetrahydrofuran. Treatment of the intermediate 2-hydroxybenzyl alcohol19 with an oxidizing agent such as manganese (IV) oxide in a solventsuch as methylene chloride or chloroform provides salicylaldehyde 1.

[0643] Synthetic Scheme 9 illustrates a general synthetic method forpreparation of a wide variety of substituted2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acids (25). In step1, an appropriately commercially or synthetically available substitutedthiophenol 22 is ortho-metallated with a base such as n-butyllithiumemploying TMEDA (N,N,N′,N′-tetramethylethylenediamine) followed bytreatment with dimethylformamide to provide the 2-mercaptobenzaldehyde23. Condensation of the 2-mercaptobenzaldehyde 23 with an acrylate 2 inthe presence of base provides ester 24 which can be saponified in thepresence of aqueous base to afford the substituted2H-1-benzothiopyran-3-carboxylic acids 25.

[0644] Synthetic Scheme 10 shows a method for preparing a substituted2-mercaptobenzaldehyde from an appropriate commercially or syntheticallyavailable substituted salicylaldehyde. In step 1, the phenolic hydroxylof salicylaldehyde 1 is converted to the corresponding O-arylthiocarbamate 26 by acylation with an appropriately substitutedthiocarbamoyl chloride such as N,N-dimethylthiocarbamoyl chloride in asolvent such as dimethylformamide using a base such as triethylamine. InStep 2, O-aryl thiocarbamate 26 rearranges to S-aryl thiocarbamate 27when heated sufficiently such as to 200° C. using either no solvent or asolvent such as N,N-dimethylaniline (See: A. Levai, and P. Sebok, Synth.Commun., 22 1735-1750 (1992)). Hydrolysis of S-aryl thiocarbamate 27with a base such as 2.5 N sodium hydroxide in a solvent mixture such astetrahydrofuran and ethanol yields the substituted2-mercaptobenzaldehyde 23 which can be converted to the substituted2H-1-benzothiopyran-3-carboxylic acids 25 as described in Scheme 9.

[0645] Synthetic Scheme 11 illustrates the general method for thepreparation of a wide variety of dihydroquinoline-3-carboxylic acidderivatives 30. R² represents the aromatic substitution of commerciallyand synthetically available 2-aminobenzaldeydes 28. The2-amino-benzaldehyde derivative 28, where R² represents varioussubstitutions, is condensed with a acrylate derivative 2 in the presenceof base such as potassium carbonate, triethylamine, ordiazbicyclo[2.2.2]undec-7-ene in solvents such as dimethylformamide toafford the dihydroquinoline-3-carboxylate esters 29. The ester 29 can besaponified to the corresponding acid, such as by treatment with aqueousinorganic base such as 2.5 N sodium hydroxide in a suitable solvent suchas ethanol to afford after acidification the desireddihydroquinoline-3-carboxylic acid 30.

[0646] Synthetic Scheme 12 illustrates the preparation ofdihydroquinoline-3-carboxylic acid 30 from 2-aminobenzoic acids 31. R²represents the aromatic substitution of commercially and syntheticallyavailable 2-aminobenzoic acids 31. Reduction of the representative2-aminoberizoic acid 31 to the desired 2-aminobenzyl alcohol 32 wasaccomplished with a hydride reducing agent such as borane in a solventsuch as tetrahydrofuran. Treatment of the desired 2-aminobenzyl alcohol32 with an oxidizing agent such as manganese (IV) oxide in a solventsuch as methylene chloride provides the representative2-aminobenzaldehydes 28. (C. T. Alabaster, et al. J. Med. Chem. 31,2048-2056 (1988)) The 2-aminobenzaldehydes were converted to the desireddihydroquinoline-3-carboxylic acid 30 as described in Scheme 11.

[0647] Synthetic Scheme 13 illustrates the general method f or thepreparation of a wide variety of dihydroquirioline-3-carboxylic acidderivatives 30 from isatins 33. R² represents the aromatic substitutionof commercially and synthetically available isatins 33. A representativeisatin 33 was treated with basic peroxide generated from hydrogenperoxide and a base such as sodium hydroxide to afford the desiredrepresentative 2-aminobenzoic acids 31. (M. S. Newman and M. W. Lougue,J. Org. Chem., 36, 1398-1401 (1971)) The 2-aminobenzoic acids 31 aresubsequently converted to the desired dihydroquinoline-3-carboxylic acidderivatives 30 as described in synthetic Scheme 12.

[0648] Synthetic Scheme 14 is another general method for the preparationof dihydroquinoline-3-carboxylic acid derivatives 30. In step 1, anappropriate commercially or synthetically available substituted aniline34 can be treated with an acylating reagent such as pivaloyl chlorideyielding an amide 35. The ortho-dianion of amide 35 is prepared bytreating amide 35 with organo-lithium bases such as n-butyllithium ortert-butyllithium in tetrahydrofuran at low temperature. The dianion isquenched with dimethylformamide to afford theacylated-2-amino-benzaldehydes 36. (J. Turner, J. Org. Chem., 48,3401-3408 (1983)) Reaction of these aldehydes in the presence of basessuch as lithium hydride with a acrylate followed by work up with aqueousinorganic bases and hydrolysis, such as by treatment with aqueous base(sodium hydroxide) in a suitable solvent such as ethanol affords, afteracidification, a dihydroquinoline-3-carboxylic acid 30.

[0649] Synthetic Scheme 15 shows a general method for alkylation of thenitrogen of dihydroquinoline-3-carboxylate ester derivatives 29. Thestep involves treatment of dihydroquinoline-3-carboxylate esterderivatives 29 with alkyl halides such as iodoethane in the presence ofphase transfer catalysts such a tetrabutylammonium iodide, and a basesuch as caustic (50% aqueous sodium hydroxide) in a solvent such asdichloromethane. These conditions afford the N-alkylateddihyrdoquinoline-3-carboxylate esters 37. Saponif ication of 37 withaqueous base provides N-alkylated-dihyroquinoline-3-carboxylic acidderivatives 38.

[0650] Synthetic Scheme 16 shows a general method for the preparation ofa 7-ether (Z¹=O) or thioether (Z¹=S) substituted benzopyran-3-carboxylicester. An appropriately substituted phenol, thiophenol,hydroxy-heterocycle, mercaptoheterocycle, alcohol, or alkylthiol can becondensed under basic conditions using a base such as potassiumcarbonate in a solvent such as dimethysulfoxide, at temperature aboveroom temperature, such as 100° C., with an appropriately substituted7-fluorobenzopyran derivative 30 to yield the corresponding ether orthioether. Hydrolysis of the ester with an aqueous base such as lithiumhydroxide or sodium hydroxide in a solvent mixture such astetrahydrofuran-ethanol-water yields acid 40. When appropriate, athioether (Z²=S) can be oxidized to the sulfoxide (Z²=SO) or sulfone(Z²=SO₂) with an oxidant such as OXONE® or m-CPBA either before or afterester hydrolysis. In this chemistry R^(d) can include aryl, heteroaryl,heterocyclic, alicyclic, branched or linear aliphatic, branched orlinear per fluoro-aliphatic moiety.

[0651] Synthetic Scheme 17 shows the general method for preparingselected 3,4-dihydrobenzopyrans (X=0), 3,4-dihydrobenzothiopyrans (X═S)or 1,2,3,4-tetrahydroquinolines (X═NH or NR^(a) wherein R^(a) is aspreviously defined). For example, treatment of an appropriatelysubstituted 2H-1-benzopyran-3-carboxylic acid 41 (X═O),2H-1-benzothiopyran-3-carboxylic acid 41 (X═S) or a1,2-dihydroquinoline-3-carboxylic acid 41 (X═NH or NR^(a)) (wherein R¹,R² and R′ are as previously defined) with an appropriate reducing agentyields the corresponding substituted 3,4-dihydrobenzopyran 42 (X═O),substituted 3,4-dihydrobenzothiopyran-3-carboxylic acid 42 (X═S), orsubstituted 1,2,3,4-tetrahydroquinoline-3-carboxylic acid 42 (X═NR^(a)),respectively. Suitable reducing agents include hydrogenation catalystssuch as palladium (Pd on carbon), platinum (IV) oxide (PtO₂) anddissolving metal reductions utilizing zinc-HCl or sodium-mercuryamalgam. Purification of the racemic mixture yields the isomers 43.

[0652] The following examples contain detailed descriptions of themethods of preparation of compounds of Formulas I-IV. These detaileddescriptions fall within the scope, and serve to exemplify, the abovedescribed General Synthetic Procedures which form part of the invention.These detailed descriptions are presented for illustrative purposes onlyand are not intended as a restriction on the scope of the invention. Allparts are by weight and temperatures are in Degrees centigrade unlessotherwise indicated. All compounds showed NMR spectra consistent withtheir assigned structures.

[0653] The following abbreviations are used:

[0654] HCl—hydrochloric acid

[0655] TFA—trifluoroacetic acid

[0656] CH₃CN—acetonitrile

[0657] MgSO₄— magnesium sulfate

[0658] h—hour

[0659] THF—tetrahydrofuran

EXAMPLE 1

[0660]

[0661] rel-(2R,3S)-6,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carbolicAcid

[0662] 6,8-Dichloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylicacid, prepared as described in WO98/47890, (0.32 g, 0.97 mmol) wasplaced in a Fisher & Porter™ tube with THF (30 mL), and platinium (IV)oxide (0.47 g). The tube was pressurized to 34 psi with hydrogen gas andthe reaction mixture stirred at room temperature for about 23 hours. Thereaction mixture was filtered through diatomaceous earth, concentratedin vacuo and passed through a column of silica gel with ethylacetate-hexane-acetic acid (20:80:2) as the eluent, to give a whitesolid which was recrystallized from isooctane-hexane yielding a whitecrystalline solid (0.10 g, 31%): mp 165.0-170.2° C. ¹H NMR(acetone-d₆/300 MHz) 7.34 (s, 1H), 7.28 (s, 1H), 4.63-4.69 (m, H), 3.40(d, 1H, J=13.5 Hz), 3.29 (d, 1H, J=18.1 Hz), 3.04-3.16 (m, 1H). ¹⁹F NMR(acetone-d₆/282 MHz)-67.3 (d, J=8.7 Hz). FABLRMS m/z 329 (M−H). ESHRMSn/z 347.9830 (M+NH₄, Calc'd 347.9840). Anal. Calc'd for C₁₁H₇Cl₂F₃O₂S:C, 39.90; H, 2.13; Cl, 21.41. Found: C, 40.01; H, 1.74; Cl, 21.70.

EXAMPLE 2

[0663]

[0664] (2S,3R)-6,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicAcid.

[0665] A 500 mL Parr™ shaker bottle was charged with platinum (IV) oxide(2.99 g) and acetic acid (120 mL) pressurized with hydrogen gas (50 psi)and shaken for 0.75 hours. The hydrogen was vented and the reactor wascharged with(2S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid(10.21 g, 32.62 mmol) and pressurized with hydrogen gas (25 psi). After3 h, the reactor was vented, additional platinum (IV) oxide (1.59 g) wasadded, the reactor was pressurized with hydrogen gas (25 psi) and shakenfor 2 h longer. The crude product mixture was filtered throughdiatomaceous earth and the filtrate concentrated in vacuo.

[0666] The resulting crude product was purified by flash silicachromatography (hexanes-ethyl acetate, 3:1) followed by reverse phasechromatography [C₁₈ stationary phase, CH₃CN—H₂O with 0.1% TFA (gradient15:85 to 50:50)] providing 5.02 g of a white, oily foam. This foam wasfurther purified by flash silica chromatography (hexanes-ethyl acetatewith 2% acetic acid (gradient 4:1 to 0:1) and crystallization frommethylene chloride-isooctane (1:10) followed by further purification byreverse phase chromatography [CH₃CN—HO with 0.1% TFA (gradient 15:85 to45:65)] yielding 2.3 g of a sticky foam. This foam was crystallized frommethylene chloride-isooctane (1:10) at room temperature yielding thedesired product (1.50 g) as fine white clear needles: mp 100.3-101.1° C.¹H NMR (acetone-d₆ with TFA/400 MHz) 7.33 (d, 1H, J=2.4 Hz), 7.25 (d,1H, J=2.4 Hz), 5.31-5.22 (m, 1H), 3.59-3.51 (m 1H), 3.16 (dd, 1H, J=6.2,17.5 Hz), 3.10 (dd, 1H, J=8.1, 17.5 Hz) LRMS m/z 313 (M−H). HRMS m/z312.9632 (M−H, C₁₁H₆Cl₂F₃O₃ requires 312.9646). Anal. Calc'd forC₁₁H₇Cl₂F₃O₃+0.77 wt % H₂O: C, 41.61; H, 2.31; Cl, 22.33. Found: C,41.74; H, 2.22; Cl, 22.05.

EXAMPLE 3

[0667]

[0668] rel-(2R,3S)-5,6-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicAcid

[0669] Prepared by a procedure similar to that described in EXAMPLE 1.mp 173.0-174.4° C. ¹H NMR (acetone-d6/300 MHz) 7.43 (d, 1H, J=8.9 Hz),7.03 (d, 1H, J=8.9 Hz), 5.19-5.22 (m, 1H), 3.59-3.69 (m, 1H), 3.23 (dd,1H, J=17.9 Hz, 6.2 Hz), 3.13 (dd, 1H, J=17.9 Hz, 7.5 Hz). ¹⁹F NMR(acetone-d₆/282 MHz)-74.5 (d, J=7.2 Hz). FABLRMS m/z 313 (M−H). ESHRMSm/z 312.9635 (M−H, Calc'd 312.9646). Anal. Calc'd for C₁₁H₇Cl₂F₃O₃: C,41.93; H, 2.24. Found: C, 41.52; H, 2.53.

EXAMPLE 4

[0670]

[0671] (2S,3R)-6-chloro-3,4-dihydro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicAcid

[0672] Prepared by a procedure similar to that described in EXAMPLE 1.mp 115.8-120.9° C. ¹H NMR (acetone-d₆/300 MHz) 7.23 (s, 1H), 7.02 (s,1H), 5.10-5.16 (m, 1H), 3.48-3.58 (m, 1H), 3.05-3.20 (m, 2H). ¹⁹F NMR(acetone-d₆/282 MHz)-74.3 (d, J=6.5 Hz). ESHRMS m/z 335.0658 (M−H,Calc'd 335.0661). Anal. Calc'd for C₁₅H₁₆ClF₃O₃: C, 53.50; H, 4.79; Cl,10.53. Found: C, 53.19; H, 4.83; Cl, 10.20.

EXAMPLE 5

[0673]

[0674]rel-(2R,3S)-3,4-dihydro-5,6,7-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicAcid

[0675] A solution of6,7,8-trichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid(0.28 g, 0.81 mmol, prepared as described in WO98/47890, in ethanol (10mL) was treated with concentrated HCl (5 mL) and zinc powder (1.21 g,18.5 mmol). The mixture was stirred at room temperature for 3 hours,filtered, and concentrated in vacuo. The residue was extracted withethyl acetate, washed with brine, dried over MgSO₄, and concentrated invacuo to give a white solid (0.31 g) which was a 3:2 mixture of cis andtrans isomers. The isomers were separated by reverse phase HPLC toobtain the desired cis isomer as a white solid (0.11 g, 39%): mp207.3-208.5° C. ¹H NMR (acetone-d₆/300 MHz) 7.23 (s, 1H), 5.17-5.31 (m,1H), 3.58-3.72 (m, 1H), 3.19 (dd, 1H, J=17.9 Hz, 6.5 Hz), 3.10 (dd, 1H,J=17.9 Hz, 7.7 Hz) ¹⁹F NMR (acetone-d₆/282 MHz)-74.6 (d, J=7.2 Hz).ESHRMS m/z 346.9270 (M−H, Calc'd 346.9256). Anal. Calc'd forC₁₁H₆Cl₃F₃O₃: C, 37.80; H, 1.73; Cl, 30.43. Found: C, 37.66; H, 1.75;Cl, 30.71.

EXAMPLE 6

[0676]

[0677] (2S,3R)-6-Chloro-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicAcid

[0678] Prepared by a procedure similar to that described in EXAMPLE 5.mp 154.4-154.5° C. ¹H NMR (acetone-d₆/300 MHz) 7.09 (s, 1H), 7.00 (dd,1H, J=8.7 Hz, 2.4 Hz), 6.77 (d, 1H, J=8.7 Hz), 6.23 (br s, 1H),4.50-4.66 (m, 1H), 3.17-3.30 (m, 1H), 2.90-3.09 (m, 2H). ¹⁹F NMR(acetone-d₆/282 MHz)-72.5 (d, J=8.0 Hz). ESHRMS m/z 280.0351 (M+H,Calc'd 280.0352). Anal. Calc'd for C₁₁H₉ClF₃NO₂: C, 47.25; H, 3.24; N,5.01; Cl, 12.68. Found: C, 46.92; H, 3.05; N, 4.96; Cl, 12.80.

EXAMPLE 7

[0679]

[0680] rel-(2R,3S)-3,4-dihydro-6,7,8-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicAcid

[0681] Prepared by a procedure similar to that described in EXAMPLE 5.mp 205.2-208.1° C. ¹H NMR (acetone-d₆/300 MHz) 7.46 (s, 1H, J=0.8 Hz),5.28-5.38 (m, 1H), 3.56-3.63 (m, 1H), 3.25. (dd, 1H, J=17.7 Hz, 6.0 Hz),3.16 (dd, 1H, J=17.5 Hz, 7.7 Hz). ¹⁹F NMR (acetone-d6/282 MHz)-74.8 (d,J=6.5 Hz). ESHRMS m/z 346.9249 (M−H, Calc'd 346.9256). Anal. Calc'd forC₁₁H₆Cl₃F₃O₃: C, 37.80; H, 1.73; Cl, 30.43. Found: C, 37.69; H, 1.49;Cl, 30.33.

EXAMPLE 8

[0682]

[0683] (racemic; ca. 85% s-cis, 15% s-trans)

[0684]rel-(2R,3S)-5,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicAcid

[0685] Prepared by a procedure similar to that described in EXAMPLE 5.mp 185.7-188.9° C. ¹H NMR (acetone-d₆/300 MHz) 7.33 (d, 1H, J=8.7 Hz),7.14 (d, 1H, J=8.5 Hz), 5.20-5.37 (m, 1H), 3.65 (m, 1H), 3.19 (dd, 1H,J=17.7 Hz, 6.3 Hz), 3.09 (dd, 1H, J=17.7 Hz, 7.9 Hz). ¹⁹F NMR(acetone-d₆/282 MHz)-74.5 (d, J=7.1 Hz). FABLRMS m/z 313 (M−H). ESHRMSzn/z 312.9645 (M−H, Calc'd 312.9646). Anal. Calc'd for C₁₁H₇Cl₂F₃O₃: C,41.93; H, 2.24; Cl, 22.50. Found: C, 41.93; H, 2.15; Cl, 22.31.

EXAMPLE 9

[0686]

[0687](2S,3R)-6-chloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicAcid

[0688] Prepared by a procedure similar to that described in EXAMPLE 5.mp 118.1-119.2° C. ¹H NMR (acetone-d₆/300 MHz) 7.24 (s, 1H), 7.16 (d,1H, J=8.7 Hz), 6.94 (d, 1H, J=8.7 Hz), 5.10-5.22 (m, 1H), 3.45-3.58 (m,1H) 3.01-3.22 (m, 2H). ¹⁹F NMR (acetone-d₆/282 MHz)-74.4 (d, J=7.2 Hz).ESHRMS m/z 279.0005 (M−H, Calc'd 279.0036). Anal. Calc'd forC₁₁H₈ClF₃O₃: C, 47.08; H, 2.87; Cl, 12.63. Found: C, 46.87; H, 2.79; Cl,12.52.

EXAMPLE 10

[0689]

[0690] (racemic: ca. 93% s-cis, 7% s-trans)

[0691]rel-(2R,3S)-6-cyano-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[0692] Prepared by a procedure similar to that described in EXAMPLE 5.mp 169.0-170.4° C. ¹H NMR (acetone-d₆/300 MHz) 7.70 (s, 1H), 7.60 (d,1H, J=8.5 Hz), 7.14 (d, 1H, J=8.5 Hz), 5.24-5.37 (m, 1H), 3.55-3.67 (m,1H) 3.26 (dd, 1H, J=17.2 Hz, 5.9 Hz), 3.19 (dd, 1H, J=17.5 Hz, 8.3 Hz).¹⁹F NMR (acetone-d₆/282 MHz)-74.6 (d, J=7.2 Hz). ESHRMS m/z 270.0365(M−H, Calc'd 270.0378). Anal. Calc'd for C₁₂H₈F₃NO₃: C, 53.15; H, 2.97;N, 5.16. Found: C, 52.89; H, 2.73; N, 5.13.

EXAMPLE 11

[0693]

[0694] (racemic)

[0695]rel-(2R,3S)-3,4-dihydro-6-trifluoromethoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicAcid

[0696] Prepared by a procedure similar to that described in EXAMPLE 5.mp 120.1-120.8° C. ¹H NMR (acetone-d₆/300 MHz) 7.25 (s, 1H), 7.16 (d,1H, J=8.9 Hz), 7.06 (d, 1H, J=8.9 Hz), 5.15-5.28 (m, 1H), 3.51-3.61 (m,1H) 3.23 (dd, 1H, J=17.3 Hz, 5.9 Hz), 3.17 (dd, 1H, J=17.3 Hz, 8.5 Hz).¹⁹F NMR (acetone-d₆/282 MHz)-59.4 (s, 3F), −74.5 (d, 3F, J=7.2 Hz).ESHRMS m/z 329.0288 (M−H, Calc'd 329.0249). Anal. Calc'd for C₁₂H₈F₆O₄:C, 43.65; H, 2.44. Found: C, 43.87; H, 2.33.

Biological Evalation

[0697] Rat Carrageenan Foot Pad Edema Test

[0698] The carrageenan foot edema test was performed with materials,reagents and procedures essentially as described by Winter, et al.,(Proc. Soc. Exp. Biol. Med., 111, 544 (1962)). Male Sprague-Dawley ratswere selected in each group so that the average body weight was as closeas possible. Rats were fasted with free access to water for over sixteenhours prior to the test. The rats were dosed orally (1 mL) withcompounds suspended in vehicle containing 0.5% methylcellulose and0.025% surfactant, or with vehicle alone. One hour later a subplantarinjection of 0.1 mL of 1% solution of carrageenan/sterile 0.9% salinewas administered and the volume of the injected foot was measured with adisplacement plethysmometer connected to a pressure transducer with adigital indicator. Three hours after the injection of the carrageenan,the volume of the foot was again measured. The average foot swelling ina group of drug-treated animals was compared with that of a group ofplacebo-treated animals and the percentage inhibition of edema wasdetermined (Otterness and Bliven, Laboratory Models for Testing NSAIDs,in Non-steroidal Anti-Inflammatory Drugs, (J. Lombardino, ed. 1985)).The % inhibition shows the % decrease from control paw volume determinedin this procedure and the data for selected compounds in this inventionare summarized in Table I. TABLE I RAT PAW EDEMA ANALGESIA % Inhibition% Inhibition Example @ 30 mg/kg body weight @ 30 mg/kg body weight 2 5256

[0699] Evaluation of COX-1 and COX-2 Activity In Vitro

[0700] The compounds of this invention exhibited inhibition in vitro ofCOX-2. The COX-2 inhibition activity of the compounds of this inventionillustrated in the Examples was determined by the following methods.

[0701] a. Preparation of Recombinant COX Baculoviruses

[0702] Recombinant COX-1 and COX-2 were prepared as described by Gierseet al, [J. Biochem., 305, 479-84 (1995)]. A 2.0 kb fragment containingthe coding region of either human or murine COX-1 or human or murineCOX-2 was cloned into a BamHI site of the baculovirus transfer vectorpVL1393 (Invitrogen) to generate the baculovirus transfer vectors forCOX-1 and COX-2 in a manner similar to the method of D. R. O'Reilly etal (Baculovirus Expression Vectors: A Laboratory Manual (1992)).Recombinant baculoviruses were isolated by transfecting 4 μg ofbaculovirus transfer vector DNA into SF9 insect cells (2×10⁸) along with200 ng of linearized baculovirus plasmid DNA by the calcium phosphatemethod. See M. D. Summers and G. E. Smith, A Manual of Methods forBaculovirus Vectors and Insect Cell Culture Procedures, Texas Agric.Exp. Station Bull. 1555 (1987). Recombinant viruses were purified bythree rounds of plaque purification and high titer (10⁷-10⁸ pfu/mL)stocks of virus were prepared. For large scale production, SF9 insectcells were infected in 10 liter fermentors (0.5×10⁶/mL) with therecombinant baculovirus stock such that the multiplicity of infectionwas 0.1. After 72 hours the cells were centrifuged and the cell pellethomogenized in Tris/Sucrose (50 mM: 25%, pH 8.0) containing 1%3-[(3-cholamidopropyl) dimethylammino]-1-propanesulfonate (CHAPS). Thehomogenate was centrifuged at 10,000×G for 30 minutes, and the resultantsupernatant was stored at −80° C. before being assayed for COX activity.

[0703] b. Assay for COX-1 and COX-2 Activity

[0704] COX activity was assayed as PGE₂ formed/Ag protein/time using anELISA to detect the prostaglandin released. CHAPS-solubilized insectcell membranes containing the appropriate COX enzyme were incubated in apotassium phosphate buffer (50 mM, pH 8.0) containing epinephrine,phenol, and heme with the addition of arachidonic acid (10 AM).Compounds were pre-incubated with the enzyme for 10-20 minutes prior tothe addition of arachidonic acid. Any reaction between the arachidonicacid and the enzyme was stopped after ten minutes at 37° C./roomtemperature by transferring 40 Al of reaction mix into 160 Al ELISAbuffer and 25 μM indomethacin. The PGE₂ formed was measured by standardELISA technology (Cayman Chemical). Results are shown in Table II.

[0705] c. Fast assay for COX-1 and COX-2 Activity

[0706] COX activity was assayed as PGE₂ formed/μg protein/time using anELISA to detect the prostaglandin released. CHAPS-solubilized insectcell membranes containing the appropriate COX enzyme were incubated in apotassium phosphate buffer (0.05 M Potassium phosphate, pH 7.5, 2 μMphenol,1 μM heme, 300 μM epinephrine) with the addition of 20 μl of 100μM arachidonic acid (10 μM). Compounds were pre-incubated with theenzyme for 10 minutes at 25° C. prior to the addition of arachidonicacid. Any reaction between the arachidonic acid and the enzyme wasstopped after two minutes at 37° C./room temperature by transferring 40μl of reaction mix into 160 μl ELISA buffer and 25 μM indomethacin. ThePGE₂ formed was measured by standard ELISA technology (Cayman Chemical).Results are shown in Table II. TABLE II COX-2* COX-1* COX-2 COX-1Example IC₅₀ μM IC₅₀ μM IC₅₀ μM IC₅₀ μM 1 0.6 0.6 0.3 0.6 2 0.3 1.0 0.22.8 3 0.2 5.7 0.2 >100 4 1.6 1.3 >100 12 5 0.4 >100 0.4 >100 6 2.6 >10025 >100 7 0.6 54 0.7 >100 8 2.3 8.7 2.0 22 9 0.5 >100 29 >100 104.8 >100 18 >100 11 0.6 65 0.4 >100

[0707] Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of Formula I in associationwith one or more non-toxic, pharmaceutically-acceptable carriers and/ordiluents and/or adjuvants (collectively referred to herein as “carrier”materials) and, if desired, other active ingredients. The activecompounds of the present invention may be administered by any suitableroute, preferably in the form of a pharmaceutical composition adapted tosuch a route, and in a dose effective for the treatment intended. Theactive compounds and composition may, for example, be administeredorally, pulmonary, mucosally, intravascularly, intraperitoneally,subcutaneously, intramuscularly or topically.

[0708] The phrase “co-therapy” (or “combination-therapy”), in defininguse of a cyclooxygenase-2 inhibitor agent and another pharmaceuticalagent, is intended to embrace administration of each agent in asequential manner in a regimen that will provide beneficial effects ofthe drug combination, and is intended as well to embraceco-administration of these agents in a substantially simultaneousmanner, such as in a single capsule having a fixed ratio of these activeagents or in multiple, separate capsules for each agent.

[0709] The phrase “therapeutically-effective” is intended to qualify theamount of each agent which will achieve the goal of improvement indisease severity and the frequency of incidence over treatment of eachagent by itself, while avoiding adverse side effects typicallyassociated with alternative therapies.

[0710] For oral administration, the pharmaceutical composition may be inthe form of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. The active ingredient mayalso be administered by injection as a composition wherein, for example,saline, dextrose or water may be used as a suitable carrier.

[0711] The amount of therapeutically active compounds which areadministered and the dosage regimen for treating a disease conditionwith the compounds and/or compositions of this invention depends on avariety of factors, including the age, weight, sex and medical conditionof the subject, the severity of the disease, the route and frequency ofadministration, and the particular compound employed, and thus may varywidely. The pharmaceutical compositions may contain active ingredientsin the range of about 0.1 to 2000 mg, preferably in the range of about0.5 to 500 mg and most preferably between about 1 and 100 mg. A dailydose of about 0.01 to 100 mg/kg body weight, preferably between about0.5 and about 20 mg/kg body weight and most preferably between about 0.1to 10 mg/kg body weight, may be appropriate. The daily dose can beadministered in one to four doses per day.

[0712] In the case of psoriasis and other skin conditions, it may bepreferable to apply a topical preparation of compounds of this inventionto the affected area two to four times a day.

[0713] For inflammations of the eye or other external tissues, e.g.,mouth and skin, the formulations are preferably applied as a topicalointment or cream, or as a suppository, containing the activeingredients in a total amount of, for example, 0.075 to 30% w/w,preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither paraffinic or a water-miscible ointment base. Alternatively, theactive ingredients may be formulated in a cream with an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example at least 30% w/w of a polyhydric alcohol such as propyleneglycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethyleneglycol and mixtures thereof. The topical formulation may desirablyinclude a compound which enhances absorption or penetration of theactive ingredient through the skin or other affected areas. Examples ofsuch dermal penetration enhancers include dimethylsulfoxide and relatedanalogs. The compounds of this invention can also be administered by atransdermal device. Preferably topical administration will beaccomplished using a patch either of the reservoir and porous membranetype or of a solid matrix variety. In either case, the active agent isdelivered continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

[0714] The oily phase of the emulsions of this invention may beconstituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others.

[0715] The choice of suitable oils or fats for the formulation is basedon achieving the desired cosmetic properties, since the solubility ofthe active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palpitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

[0716] Formulations suitable for topical administration to the eye alsoinclude eye drops wherein the active ingredients are dissolved orsuspended in suitable carrier, especially an aqueous solvent for theactive ingredients. The antiinflammatory active ingredients arepreferably present in such formulations in a concentration of 0.5 to20%, advantageously 0.5 to 10% and particularly about 1.5% w/w.

[0717] For therapeutic purposes, the active compounds of thiscombination invention are ordinarily combined with one or more adjuvantsappropriate to the indicated route of administration. If administeredper os, the compounds may be admixed with lactose, sucrose, starchpowder, cellulose esters of alkanoic acids, cellulose alkyl esters,talc, stearic acid, magnesium stearate, magnesium oxide, sodium andcalcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, andthen tableted or encapsulated for convenient administration. Suchcapsules or tablets may contain a controlled-release formulation as maybe provided in a dispersion of active compound in hydroxypropylmethylcellulose. Formulations for parenteral administration may be in the formof aqueous or non-aqueous isotonic sterile injection solutions orsuspensions. These solutions and suspensions may be prepared fromsterile powders or granules having one or more of the carriers ordiluents mentioned for use in the formulations for oral administration.The compounds may be dissolved in water, polyethylene glycol, propyleneglycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvantsand modes of administration are well and widely known in thepharmaceutical art.

[0718] For pulmonary administration, the pharmaceutical composition maybe administered in the form of an aerosol or with an inhaler includingdry powder aerosol.

[0719] All mentioned references are incorporated by reference as if herewritten.

[0720] Although this invention has been described with respect tospecific embodiments, the details of these embodiments are not to beconstrued as limitations.

What is claimed is:
 1. A compound of Formula I

wherein X is selected from O, S, CR^(c)R^(b) and NR^(a); wherein R^(a)is selected from hydrido, C₁-C₃-alkyl, phenyl-C₁-C₃-alkyl,(substitutedphenyl)-C₁-C₃-alkyl, C₁-C₃-alkoxycarbonyl-C₁-C₃-alkyl andcarboxy-C₁-C₆-alkyl; wherein each of R^(b) and R^(c) is independentlyselected from hydrido, C₁-C₃-alkyl, substituted or unsubstitutedphenyl-C₁-C₃-alkyl, C₁-C₃-perfluoroalkyl, chloro, C₁-C₆-alkylthio,C₁-C₆-alkoxy, nitro, cyano and cyano-C₁-C₃-alkyl; or wherein CR^(b)R^(c)forms a 3-6 membered cycloalkyl ring; wherein R is selected fromcarboxyl, aminocarbonyl, C₁-C₆-alkylsulfonylaminocarbonyl andC₁-C₆-alkoxycarbonyl; wherein R″ is selected from hydrido, phenyl,thienyl, C₁-C₆-alkyl and C₂-C₆-alkenyl; wherein R¹ is selected fromC₁-C₃-perfluoroalkyl, chloro, C₁-C₆-alkylthio, C₂-C₆-alkoxy, nitro,cyano and cyano-C₁-C₃-alkyl; wherein R² is one or more radicalsindependently selected from hydrido, halo, C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, halo-C₂-C₆-alkynyl, aryl-C₁-C₃-alkyl, aryl-C₂-C₆-alkynyl,aryl-C₂-C₆-alkenyl, C₁-C₆-alkoxy, methylenedioxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, aryl-C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkoxy,aryl-C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,C₁-C₆-haloalkylthio, C₁-C₆-haloalkylsulfinyl, C₃-C₆-haloalkylsulfonyl,C₁-C₃-(haloalkyl) —C₁-C₃-hydroxyalkyl, C₁-C₆-hydroxyalkyl,hydroxyimino-C₁-C₆-alkyl, C₁-C₆-alkylamino, arylamino,N-aryl-N—C₁-C₆-alkylamino, heteroarylamino,N-heteroaryl-N—C₁-C₆-alkylamino, nitro, cyano, amino, aminosulfonyl,C₁-C₆-alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl,N-aryl-C₁-C₆-alkylaminosulfonyl, N-heteroaryl-C₁-C₆-alkylaminosulfonyl,heterocyclylsulfonyl, C₁-C₆-alkylsulfonyl, aryl-C₁-C₆-alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aryl-C₁-C₆-alkylcarbonyl, heteroaryl-C₁-C₆-alkylcarbonyl,heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C₁-C₆-alkoxycarbonyl,formyl, C₁-C₆-haloalkylcarbonyl and C₁-C₆-alkylcarbonyl; and wherein theA ring atoms A¹, A², A³ and A⁴ are independently selected from carbonand nitrogen with the proviso that at least two of A¹, A² A³ and A⁴ arecarbon; or wherein R² together with ring A forms a radical selected fromnaphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl anddibenzofuryl; or an isomer or pharmaceutically acceptable salt thereof.2. A compound of claim 1 wherein X is selected from O, S, CR^(c)R^(b)and NR^(a); wherein R^(a) is selected from hydrido, C₁-C₃-alkyl,phenyl-C₁-C₃-alkyl, (substituted phenyl) —C₁-C₃-alkyl,C₁-C₃-alkoxycarbonyl-C₁-C₃-alkyl and carboxy-C₁-C₆-alkyl; wherein eachof R^(b) and R^(c) is independently selected from hydrido, C₁-C₃-alkyl,phenyl-C₁-C₃-alkyl, (substituted phenyl)-C₁-C₃-alkyl,C₁-C₃-perfluoroalkyl, chloro, C₁-C₄-alkylthio, C₁-C₄-alkoxy, nitro,cyano and cyano-C₁-C₃-alkyl; or wherein CR^(b)R^(c) forms a cyclopropylring; wherein R is selected from carboxyl, aminocarbonyl,C₁-C₄-alkylsulfonylaminocarbonyl and C₃-C₄-alkoxycarbonyl; wherein R″ isselected from hydrido, phenyl, thienyl, C₁-C₄-alkyl and C₂-C₄-alkenyl;wherein R¹ is selected from C₁-C₃-perfluoroalkyl, chloro,C₁-C₄-alkylthio, C₁-C₄-alkoxy, nitro, cyano and cyano-C₁-C₃-alkyl;wherein R² is one or more radicals independently selected from hydrido,halo, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₆-alkynyl, halo-C₂-C₆-alkynyl,aryl-C₁-C₃-alkyl, aryl-C₂-C₄-alkynyl, aryl-C₂-C₄-alkenyl, C₁-C₄-alkoxy,methylenedioxy, C₁-C₄-alkylthio, C₁-C₄-alkylsulfinyl, aryloxy, arylthio,arylsulfinyl, heteroaryloxy, C₁-C₄-alkoxy-C₁--C₄-alkyl,aryl-C₁-C₄-alkoxy, heteroaryl-C₃-C₄— alkoxy,aryl-C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy,C₁-C₄-haloalkylthio, C₁-C₄-haloalkylsulfinyl, C₁-C₄-haloalkylsulfonyl,C₁-C₃-(haloalkyl)-C₁-C₃-hydroxyalkyl, C₃-C₄-hydroxyalkyl,hydroxyimino-C₁-C₄-alkyl, C₁-C₄-alkylamino, arylamino,N-aryl-N—C₁-C₄-alkylamino, heteroarylamino,N-heteroaryl-N—C₁-C₄-alkylamino, nitro, cyano, amino, aminosulfonyl,C₁-C₄-alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl,aryl-C—C₄-alkylaminosulfonyl, heteroaryl-C₁-C₄-alkylaminosulfonyl,heterocyclylsulfonyl, C₁-C₄-alkylsulfonyl, aryl-C₁-C₄-alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aryl-C₁-C₄-alkylcarbonyl, heteroaryl-C₁-C₄-alkylcarbonyl,heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C₁-C₄-alkoxycarbonyl,formyl, C₁-C₄-haloalkylcarbonyl and C₁-C₄-alkylcarbonyl; and wherein theA ring atoms A¹, A², A³ and A⁴ are independently selected from carbonand nitrogen with the proviso that at least three of A¹, A², A³ and A⁴are carbon; or wherein R² together with ring A forms a naphthyl orquinolyl radical; or an isomer or pharmaceutically acceptable saltthereof.
 3. A compound of claim 2 wherein X is selected from O, S andNR^(a); wherein R^(a) is selected from hydrido, C₁-C₃-alkyl and(optionally substituted phenyl)methyl; wherein R is carboxyl; wherein R″is selected from hydrido, C₁-C₃-alkyl and C₂-C₃-alkenyl; wherein R¹ isselected from C₁-C₃-perfluoroalkyl; wherein R² is one or more radicalsindependently selected from hydrido, halo, C₁-C₄-alkyl, C₂-C₃-alkenyl,C₂-C₆-alkynyl, halo-C₂-C₆-alkynyl, optionally substitutedphenyl-C₁-C₃-alkyl, optionally substituted phenyl-C₂-C₃-alkynyl,phenyl-C₂-C₃-alkenyl, C₁-C₃-alkoxy, methylenedioxy,C₁-C₃-alkoxy-C₁-C₃-alkyl, C₁-C₃-alkylthio, C₁-C₃-alkylsulfinyl,optionally substituted phenyloxy, optionally substituted phenylthio,optionally substituted phenylsulfinyl,C₁-C₃-haloalkyl-C₁-C₃-hydroxyalkyl, phenyl-C₁-C₃-alkoxy-C₃-C₃-alkyl,C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, C₁-C₃-haloalkylthio,C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy-C₁-C₃-alkyl, hydroxyimino-C₁-C₃-alkyl,C₁-C₆-alkylamino, nitro, cyano, amino, aminosulfonyl,N-alkylaminosulfonyl, N-arylaminosulfonyl, N-heteroarylaminosulfonyl,N-(phenyl-C—C₆-alkyl)aminosulfonyl,N-(heteroaryl-C₁-C₆-alkyl)aminosulfonyl, phenyl-C₁-C₃-alkylsulfonyl, 5-to 8-membered heterocyclylsulfonyl, C₁-C₃-alkylsulfonyl, optionallysubstituted phenyl, optionally substituted 5- to 9-membered heteroaryl,phenyl-C₁-C₃-alkylcarbonyl, phenylcarbonyl, 4-chlorophenylcarbonyl,4-hydroxyphenylcarbonyl, 4-trifluoromethylphenylcarbonyl,4methoxyphenylcarbonyl, aminocarbonyl, formyl, and C₁-C₆-alkylcarbonyl;wherein the A ring atoms A¹, A², A³ and A⁴ are independently selectedfrom carbon and nitrogen with the proviso that at least three of A¹, A²,A³ and A⁴ are carbon; or wherein R² together with ring A forms anaphthyl, benzofurylphenyl, or quinolyl radical; or an isomer orpharmaceutically acceptable salt thereof.
 4. A compound of claim 3wherein X is selected from O, S and NR^(a); wherein R^(a) is selectedfrom hydrido, methyl, ethyl, (4-trifluoromethyl)benzyl,(4-chloromethyl)benzyl, (4-methoxy)benzyl, (4-cyano)benzyl, and(4-nitro)benzyl; wherein R is carboxyl; wherein R″ is selected fromhydrido, ethyl and ethenyl; wherein R¹ is trifluoromethyl orpentafluoroethyl; wherein R² is one or more radicals independentlyselected from hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl,ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl,3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl,4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy,methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl,pentafluoroethyl, trifluoromethoxy, trifluoromethylthio, hydroxymethyl,hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl,N-methylamino, nitro, cyano, amino, aminosulfonyl,N-methylaminosulfonyl, N-phenylaminosulfonyl, N-furylaminosulfonyl,N-(benzyl)aminosulfonyl, N-(furylmethyl)aminosulfonyl, benzylsulfonyl,phenylethylaminosulfonyl, furylsulfonyl, methylsulfonyl, phenyl, phenylsubstituted with one or more radicals selected from chloro, fluoro,bromo, methoxy, methylthio and methylsulfonyl, benzimidazolyl, thienyl,thienyl substituted with chloro, furyl, furyl substituted with chloro,benzylcarbonyl, optionally substituted phenylcarbonyl, aminocarbonyl,formyl and methylcarbonyl; wherein the A ring atoms A¹ A², A³ and A⁴ areindependently selected from carbon and nitrogen with the proviso that atleast three of A¹, A², A³ and A⁴ are carbon; or wherein R² together withring A forms a naphthyl, or quinolyl radical; or an isomer orpharmaceutically acceptable salt thereof.
 5. A compound of claim 4selected from compounds, and their isomers andpharmaceutically-acceptable salts, of the group consisting of rel-(2R,3S)-6,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid; (2S,3R)-6,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;rel-(2R,3S)-5,6-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;(2S,3R)-6-chloro-3,4-dihydro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;rel-(2R,3S)-3,4-dihydro-5,6,7-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;(2S,3R)-6-chloro-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;rel-(2R,3S)-3,4-dihydro-6,7,8-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;rel-(2R,3S)-5,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;(2S,3R)-6-chloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;rel-(2R,3S)-6-cyano-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid; andrel-(2R,3S)-3,4-dihydro-6-trifluoromethoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.
 6. A compound of Formula II

wherein R³ is selected from hydrido, C₃-C₃-alkyl, C₁-C₃-hydroxyalkyl,C₁-C₃-alkoxy and halo; wherein R⁴ is selected from hydrido, halo,C₁-C₄-alkyl, C₁-C₃-alkylthio, C₁-C₃-haloalkyl, amino, aminosulfonyl,C₁-C₃-alkylsulfonyl, C₁-C₃-alkylsulfinyl, C₁-C₃-alkoxy-C₁-C₃-alkyl,C₁-C₃-alkylcarbonyl, formyl, cyano, C₁-C₃-haloalkylthio, substituted orunsubstituted phenylcarbonyl, C₁-C₃-haloalkoxy, C₁-C₃-alkoxy,aryl-C₁-C₃-alkylcarbonyl, di-C₁-C₃-alkylaminosulfonyl,C₁-C₃-alkylaminosulfonyl, aryl-C₁-C₃-alkylaminosulfonyl, 5- or6-heteroaryl-C₁-C₃-alkylaminosulfonyl, 5- or 6-membered heteroaryl,C₁-C₃-hydroxyalkyl, substituted or unsubstituted phenyl and 5- or6-membered nitrogen-containing heterocyclylsulfonyl; wherein R⁵ isselected from hydrido, C₁-C₄-alkyl, halo, C₁-C₃-haloalkyl,C₁-C₄-hydroxyalkyl, C₂-C₃-alkynyl, C₂-C₃-alkenyl, C₁-C₃-alkoxy, phenoxy,phenoxy independently substituted with one or more radicals selectedfrom C₁-C₃-haloalkyl, nitro, carboxyl, C₁-C₃-haloalkoxy, C₁-C₃-alkoxy,cyano, C₁-C₃-alkyl and halo, naphthyloxy, naphthyloxy substituted withone or more halo radicals, phenylthio, phenylthio substituted with oneor more halo radicals, phenylsulfinyl, phenylsulfinyl substituted withone or more halo radicals, phenylsulfonyl, phenylsulfonyl substitutedwith one or more halo radicals, pyridinyloxy, pyridinyloxy substitutedwith one or more halo radicals, and phenyl; and wherein R⁶ is selectedfrom hydrido, halo, cyano, hydroxyiminomethyl, C₁-C₃-hydroxyalkyl,C₂-C₃-alkynyl, phenyl-C₂-C₃-alkynyl, C₁-C₄-alkyl, C₁-C₃-alkoxy, formyland phenyl; or an isomer or pharmaceutically acceptable salt thereof. 7.Compound of claim 6 wherein R³ is hydrido or chloro; wherein R⁴ isselected from hydrido, chloro, methyl, tert-butyl, methylthio,trifluoromethyl, difluoromethyl, pentafluoromethyl, trifluoromethylthio,trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl,and substituted or unsubstituted phenyl; wherein R⁵ is selected fromhydrido, methyl, tert-butyl, 2,2,2-trifluoroethoxy,2-hydroxy-1,1-dimethylethyl, phenoxy, 4-methoxyphenoxy, 4-chlorophenoxy,3-chlorophenoxy, 2-chlorophenoxy, 4-cyanophenoxy, 2,6-dimethylphenoxy,2,4-dichlorophenoxy, 3,4-difluorophenoxy, 4-chloro-3-fluorophenoxy,4-(trifluoromethyl)phenoxy, 4-nitrophenoxy, 4-carboxyphenoxy,3-carboxyphenoxy, 2-chloro-4-carboxyphenoxy,4-(trifluoromethoxy)phenoxy, 2-bromo-4-chlorophenoxy,(6-bromo-2-naphthalenyl)oxy, phenylthio, (4-methoxyphenyl)thio,(4-chlorophenyl)thio, (4-chlorophenyl)sulfinyl,(4-chlorophenyl)sulfonyl, (6-chloro-2-pyridinyl)oxy,(2-chloro-3-pyridinyl)oxy, (3-pyridinyl)oxy, (2-pyridinyl)oxy, iodo,ethenyl, ethynyl, chloro; and wherein R⁶ is selected from hydrido,chloro, thienyl, hydroxyiminomethyl, substituted or unsubstitutedphenylethynyl, phenyl and substituted phenyl; or an isomer orpharmaceutically acceptable salt thereof.
 8. A compound of claim 7selected from compounds, and their isomers andpharmaceutically-acceptable salts, of the group consisting of (2S,3R)-6,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;rel-(2R,3S)-5,6-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;(2S,3R)-6-chloro-3,4-dihydro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;rel-(2R,3S)-3,4-dihydro-5,6,7-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;rel-(2R,3S)-3,4-dihydro-6,7,8-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;rel-(2R,3S)-5,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;(2S,3R)-6-chloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;rel-(2R,3S)-6-cyano-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid; andrel-(2R,3S)-3,4-dihydro-6-trifluoromethoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.
 9. A compound of Formula III

wherein R^(a) is selected from hydrido and lower aralkyl; wherein R³ isselected from hydrido, C₃-C₃-alkyl, C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy andhalo; wherein R⁴ is selected from hydrido, halo, C₁-C₄-alkyl,C₁-C₃-alkylthio, C₁-C₃-haloalkyl, amino, aminosulfonyl,C₁-C₃-alkylsulfonyl, C₁-C₃-alkylsulfinyl, C₁-C₃-alkoxy-C₁-C₃-alkyl,C₁-C₃-alkylcarbonyl, formyl, cyano, C₁-C₃-haloalkylthio, substituted orunsubstituted phenylcarbonyl, C₁-C₃-haloalkoxy, C₁-C₃-alkoxy,aryl-C₁-C₃-alkylcarbonyl, di-C₁-C₃-alkylaminosulfonyl,C₁-C₃-alkylaminosulfonyl, aryl-C₁-C₃-alkylaminosulfonyl, 5- or6-heteroaryl-C₁-C₃-alkylaminosulfonyl, 5- or 6-membered heteroaryl,C₁-C₃-hydroxyalkyl, substituted or unsubstituted phenyl and 5- or6-membered nitrogen-containing heterocyclylsulfonyl; wherein R⁵ isselected from hydrido, C₃-C₄-alkyl, halo, C₁-C₃-haloalkyl,C₁-C₄-hydroxyalkyl, C₂-C₃-alkynyl, C₂-C₃-alkenyl, C₁-C₃-alkoxy, phenoxy,phenoxy independently substituted with one or more radicals selectedfrom C₁-C₃-haloalkyl, nitro, carboxyl, C₁-C₃-haloalkoxy, C₁-C₃-alkoxy,cyano, C₁-C₃-alkyl and halo, naphthyloxy, naphthyloxy substituted withone or more halo radicals, phenylthio, phenylthio substituted with oneor more halo radicals, phenylsulfinyl, phenylsulfinyl substituted withone or more halo radicals, phenylsulfonyl, phenylsulfonyl substitutedwith one or more halo radicals, pyridinyloxy, pyridinyloxy substitutedwith one or more halo radicals, and phenyl; and wherein R⁶ is selectedfrom hydrido, halo, cyano, hydroxyiminomethyl, C₁-C₃-hydroxyalkyl,C₂-C₃-alkynyl, phenyl-C₂-C₃-alkynyl, C₁-C₄-alkyl, C₁-C₃-alkoxy, formyland phenyl; or an isomer or pharmaceutically acceptable salt thereof.10. Compound of claim 9 R³ is hydrido or chloro; wherein R⁴ is selectedfrom hydrido, chloro, methyl, tert-butyl, methylthio, trifluoromethyl,difluoromethyl, pentafluoromethyl, trifluoromethylthio,trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl,and substituted or unsubstituted phenyl; wherein R⁵ is selected fromhydrido, methyl, tert-butyl, 2,2,2-trifluoroethoxy,2-hydroxy-1,1-dimethylethyl, phenoxy, 4-methoxyphenoxy, 4-chlorophenoxy,3-chlorophenoxy, 2-chlorophenoxy, 4-cyanophenoxy, 2,6-dimethylphenoxy,2,4-dichlorophenoxy, 3,4-difluorophenoxy, 4-chloro-3-fluorophenoxy,4-(trifluoromethyl)phenoxy, 4-nitrophenoxy, 4-carboxyphenoxy,3-carboxyphenoxy, 2-chloro-4-carboxyphenoxy,4-(trifluoromethoxy)phenoxy, 2-bromo-4-chlorophenoxy,(6-bromo-2-naphthalenyl)oxy, phenylthio, (4-methoxyphenyl)thio,(4-chlorophenyl)thio, (4-chlorophenyl)sulfinyl,(4-chlorophenyl)sulfonyl, (6-chloro-2-pyridinyl)oxy,(2-chloro-3-pyridinyl)oxy, (3-pyridinyl)oxy, (2-pyridinyl)oxy, iodo,ethenyl, ethynyl, chloro; and wherein R⁶ is selected from hydrido,chloro, thienyl, hydroxyiminomethyl, substituted or unsubstitutedphenylethynyl, phenyl and substituted phenyl; or an isomer orpharmaceutically acceptable salt thereof.
 11. A compound of claim 10selected from compounds, and their isomers andpharmaceutically-acceptable salts, of the group consisting of(2S,3R)-6-chloro-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid.
 12. A compound of Formula IV

wherein R³ is selected from hydrido, C₁-C₃-alkyl, C₁-C₃-hydroxyalkyl,C₁-C₃-alkoxy and halo; wherein R⁴ is selected from hydrido, halo,C₁-C₄-alkyl, C₁-C₃-alkylthio, C₁-C₃-haloalkyl, amino, aminosulfonyl,C₁-C₃-alkylsulfonyl, C₁-C₃-alkylsulfinyl, C₁-C₃-alkoxy-C₁-C₃-alkyl,C₁-C₃-alkylcarbonyl, formyl, cyano, C₁-C₃-haloalkylthio, substituted orunsubstituted phenylcarbonyl, C₁-C₃-haloalkoxy, C₁-C₃-alkoxy,aryl-C₁-C₃-alkylcarbonyl, di-C₁-C₃-alkylaminosulfonyl,C₁-C₃-alkylaminosulfonyl, aryl-C₁-C₃-alkylaminosulfonyl, 5- or6-heteroaryl-C₁-C₃-alkylaminosulfonyl, 5- or 6-membered heteroaryl,C₁-C₃-hydroxyalkyl, substituted or unsubstituted phenyl and 5- or6-membered nitrogen-containing heterocyclylsulfonyl; wherein R⁵ isselected from hydrido, C₁-C₄-alkyl, halo, C₁-C₃-haloalkyl,C₁-C₄-hydroxyalkyl, C₂-C₃-alkynyl, C₂-C₃-alkenyl, C₁-C₃-alkoxy, phenoxy,phenoxy independently substituted with one or more radicals selectedfrom C₁-C₃-haloalkyl, nitro, carboxyl, C₁-C₃-haloalkoxy, C₁-C₃-alkoxy,cyano, C₁-C₃-alkyl and halo, naphthyloxy, naphthyloxy substituted withone or more halo radicals, phenylthio, phenylthio substituted with oneor more halo radicals, phenylsulfinyl, phenylsulfinyl substituted withone or more halo radicals, phenylsulfonyl, phenylsulfonyl substitutedwith one or more halo radicals, pyridinyloxy, pyridinyloxy substitutedwith one or more halo radicals, and phenyl; and wherein R⁶ is selectedfrom hydrido, halo, cyano, hydroxyiminomethyl, C₁-C₃-hydroxyalkyl,C₂-C₃-alkynyl, phenyl-C₂-C₃-alkynyl, C₁-C₄-alkyl, C₁-C₃-alkoxy, formyland phenyl; or an isomer or pharmaceutically acceptable salt thereof.13. Compound of claim 12 R³ is hydrido or chloro; wherein R⁴ is selectedfrom hydrido, chloro, methyl, tert-butyl, methylthio, trifluoromethyl,difluoromethyl, pentafluoromethyl, trifluoromethylthio,trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl,and substituted or unsubstituted phenyl; wherein R⁵ is selected fromhydrido, methyl, tert-butyl, 2,2,2-trifluoroethoxy,2-hydroxy-1,1-dimethylethyl, phenoxy, 4-methoxyphenoxy, 4-chlorophenoxy,3-chlorophenoxy, 2-chlorophenoxy, 4-cyanophenoxy, 2,6-dimethylphenoxy,2,4-dichlorophenoxy, 3,4-difluorophenoxy, 4-chloro-3-fluorophenoxy,4-(trifluoromethyl)phenoxy, 4-nitrophenoxy, 4-carboxyphenoxy,3-carboxyphenoxy, 2-chloro-4-carboxyphenoxy,4-(trifluoromethoxy)phenoxy, 2-bromo-4-chlorophenoxy,(6-bromo-2-naphthalenyl)oxy, phenylthio, (4-methoxyphenyl)thio,(4-chlorophenyl)thio, (4-chlorophenyl)sulfinyl,(4-chlorophenyl)sulfonyl, (6-chloro-2-pyridinyl)oxy,(2-chloro-3-pyridinyl)oxy, (3-pyridinyl)oxy, (2-pyridinyl)oxy, iodo,ethenyl, ethynyl, chloro; and wherein R⁶ is selected from hydrido,chloro, thienyl, hydroxyiminomethyl, substituted or unsubstitutedphenylethynyl, phenyl and substituted phenyl; or an isomer orpharmaceutically acceptable salt thereof.
 14. A compound of claim 13,rel-(2R,3S)-6,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid, and isomers and pharmaceutically-acceptable salts, thereof.
 15. Amethod of treating or preventing a cyclooxygenase-2 mediated disorder ina subject, said method comprising treating the subject having orsusceptible to said disorder with a therapeutically-effective amount ofa compound of claims 1-14; or a pharmaceutically-acceptable saltthereof.
 16. The method of claim 15 wherein the cyclooxygenase-2mediated disorder is inflammation.
 17. The method of claim 15 whereinthe cyclooxygenase-2 mediated disorder is arthritis.
 18. The method ofclaim 15 wherein the cyclooxygenase-2 mediated disorder is pain.
 19. Themethod of claim 15 wherein the cyclooxygenase-2 mediated disorder iscancer.
 20. A pharmaceutical composition comprising atherapeutically-effective amount of a compound, said compound selectedfrom a family of compounds of claims 1-14; or apharmaceutically-acceptable salt thereof.
 21. A process for thepreparation of compounds of compound of Formula I

wherein X is selected from O, S, CR^(c)R^(b) and NR^(a); wherein R^(a)is selected from hydrido, C₁-C₃-alkyl, (optionally substitutedphenyl)-C₁-C₃-alkyl, alkoxycarbonylalkyl and carboxy-C₁-C₆-alkyl;wherein each of R^(b) and R^(c) is independently selected from hydrido,C₁-C₃-alkyl, phenyl-C₁-C₃-alkyl, C₁-C₃-perfluoroalkyl, chloro,C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro, cyano and cyano-C₁-C₃-alkyl; orwherein CR^(b)R^(c) forms a 3-6 membered cycloalkyl ring; wherein R isselected from carboxyl, aminocarbonyl, C₁-C₆-alkylsulfonylaminocarbonyland C₁-C₆-alkoxycarbonyl; wherein R″ is selected from hydrido, phenyl,thienyl, C₁-C₆-alkyl and C₂-C₆-alkenyl; wherein R¹ is selected fromC₁-C₃-perfluoroalkyl, chloro, C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro,cyano and cyano-C₁-C₃-alkyl; wherein R² is one or more radicalsindependently selected from hydrido, halo, C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, halo-C₂-C₆-alkynyl, aryl-C₁-C₃-alkyl, aryl-C₂-C₆-alkynyl,aryl-C₂-C₆-alkenyl, C₁-C₆-alkoxy, methylenedioxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, aryl-C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkoxy,aryl-C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,C₁-C₆-haloalkylthio, C₁-C₆-haloalkylsulfinyl, C₁-C₆-haloalkylsulfonyl,C₁-C₃— (haloalkyl-C₁-C₃-hydroxyalkyl, C₁-C₆-hydroxyalkyl,hydroxyimino-C₁-C₆-alkyl, C₁-C₆-alkylamino, arylamino,aryl-C₁-C₆-alkylamino, heteroarylamino, heteroaryl-C₁-C₆-alkylamino,nitro, cyano, amino, aminosulfonyl, C₁-C₆-alkylaminosulfonyl,arylaminosulfonyl, heteroarylaminosulfonyl,aryl-C₁-C₆-alkylaminosulfonyl, heteroaryl-C₁-C₆-alkylaminosulfonyl,heterocyclylsulfonyl, C₁-C₆-alkylsulfonyl, aryl-C₁-C₆-alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aryl-C₁-C₆-alkylcarbonyl, heteroaryl-C₃-C₆-alkylcarbonyl,heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C₁-C₆-alkoxycarbonyl,formyl, C₁,C₆-haloalkylcarbonyl and C₁-C₆-alkylcarbonyl; and wherein theA ring atoms A¹, A², A³ and A⁴ are independently selected from carbonand nitrogen with the proviso that at least two of A¹, A², A³ and A⁴ arecarbon; or wherein R² together with ring A forms a radical selected fromnaphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl anddibenzofuryl; or an isomer or pharmaceutically acceptable salt thereof;Said process comprising reducing a compound of Formula 41.